Ac-SDKP (N-acetyl-seryl-aspartyl-lyso-proline): organ fibrosis, tissue protection and experimental studies

Ac-SDKP (N-acetyl-seryl-aspartyl-lysinyl-proline) is an endogenous tetrapeptide formed from the larger protein, thymosin beta-4. As a result of enzymatic processing of thymosin beta-4, several fragments are formed, including Ac-SDKP [1]. This compound has attracted the interest of scientists due to the anti-fibrotic effects observed in experimental models of tissue damage. Its biological stability is limited by rapid breakdown via the angiotensin converting enzyme (ACE). In studies, it has been shown that ACE inhibitors can increase the concentration of circulating Ac-SDKP by up to fivefold, which is relevant for studies on its effects on tissues [1].

Initially, the research focused on the ability of Ac-SDKP to maintain hematopoietic stem cells in a state of relative rest. Later, the scope of the study was expanded to include inflammatory processes, remodeling of the extracellular matrix, and tissue regeneration. In several preclinical models of organ damage, the researchers observed a reduction in the pathological accumulation of matrix components. The peptide reduced, among other things, the activity of signals that stimulate cells to overproduce collagen, the main protein of the scar tissue, and limited the transformation of fibroblasts into cells responsible for scarring.

In preclinical renal studies, Ac-SDKP also showed beneficial changes in organ function and fibrosis parameters. A reduction in excessive influx of immune cells was observed, along with a weakening of inflammatory processes that can exacerbate damage. Overall, the results indicate the role of Ac-SDKP as an endogenous regulator of fibrosis-related pathways. However, observations from cell and animal studies do not confirm clinical efficacy or safety in humans.

Cardiovascular studies: heart fibrosis, inflammation, and vessel damage

Experimental cardiovascular studies analyzed Ac-SDKP in both acute myocardial injury and chronic remodeling of its structure. In a mouse model of heart attack, Nakagawa and colleagues administered Ac-SDKP at a dose of 1.6 mg/kg/day using a small subcutaneous pump. The percentage of heart wall rupture decreased from 51.0% to 27.3%, and mortality from 56.9% to 31.8%. The researchers attributed these results to a reduced influx of proinflammatory M1 macrophages, without corresponding changes in the number of M2 macrophages or neutrophils. A reduction in the activity of MMP-9, an enzyme involved in the breakdown of heart tissue after a heart attack, was also observed; however, the MPO marker remained unchanged. This may indicate a selective effect on specific damage mechanisms [2].

In studies concerning heart fibrosis caused by long-term hypertension, Peng and colleagues showed that Ac-SDKP can reduce already existing fibrous tissue, not just limit its formation. In rats with persistent hypertension, subcutaneous administration of Ac-SDKP at doses of 400–800 µg/kg per day for eight weeks reduced the collagen content in the heart in a dose-dependent manner. The higher dose resulted in a stronger effect. Systolic blood pressure did not decrease, and the normal responses to angiotensin I and bradykinin remained intact. This means that the observed changes cannot be explained solely by a reduction in blood pressure. The concentration of Ac-SDKP in the blood increased from two to five times, while the levels of TGF-β and CTGF, important mediators of fibrosis, decreased [3].

After a heart attack, persistent inflammation and fibrosis can lead to progressive organ dysfunction. Yang and colleagues studied Ac-SDKP both in the early phase to limit damage and in the later phase to assess the possibility of reversing the changes. In both cases, the total collagen content in the heart decreased. In the preventive group, for example, it decreased from approximately 24 to 15 µg/mg, while in the group investigating the reversibility of the changes, it decreased from approximately 23 to 14 µg/mg. The number of macrophages decreased by approximately one third in both groups, and the number of cells positive for TGF-β also decreased. These changes occurred without a reduction in arterial pressure and without a reduction in the heart size. In the preventive group, no significant improvement in the contractile strength was observed. Nevertheless, the reduction in fibrosis and inflammation indicated more favorable structural parameters in the studied model [4].

Ac-SDKP can also participate in additional protective effects observed during the use of ACE inhibitors. Rasoul and colleagues compared the model of hypertension caused by angiotensin II with groups receiving captopril or Ac-SDKP at doses of 400–800 µg/kg/day. The peptide increased its blood concentration several times and reproduced many effects similar to those of ACE inhibitors: it reduced excessive cell proliferation in the heart, reduced the number of macrophages and fat cells, reduced TGF-β and CTGF levels, and reduced collagen deposition. These effects occurred without reducing arterial pressure or reducing cardiac hypertrophy, suggesting a direct effect on the heart muscle tissue [5].

Rhaleb and colleagues studied Ac-SDKP in mouse heart fibroblast cultures using concentrations ranging from 0.05 to 100 nmol/l. They observed two significant effects: a reduction in cell proliferation, measured by DNA synthesis, to values close to normal at approximately 1 nmol/l, and a reduction in collagen production stimulated by endothelin-1, a potent fiber-forming mediator. Lower concentrations showed greater effectiveness in limiting collagen synthesis, while very high concentrations were less active. The mechanism appeared to be related to impaired p44/42 MAPK/ERK signaling. A known MAPK inhibitor produced a similar effect. The results are consistent with the inhibition of fibroblast proliferation and matrix synthesis through modulation of cell growth pathways [6].

In subsequent studies, it was shown that Ac-SDKP can limit heart damage caused by galectin-3. Liu and colleagues administered galectin-3, a protein associated with inflammation and fibrosis, to adult rats for four weeks. In the animals, a greater number of inflammatory cells, thickening of the heart walls, increased interstitial and perivascular fibrosis, increased activity of the TGF-β/Smad3 pathway, and impaired contractile function were observed in echocardiographic studies. By adding Ac-SDKP at a dose of 800 µg/kg/day, most of these changes were prevented. The number of inflammatory cells, fibrosis, and thickening of the heart walls were reduced, and its functional parameters were improved. The results suggest the involvement of inhibition of the TGF-β/Smad3 pathway and the reduction of inflammation [7].

Rhaleb and colleagues also evaluated Ac-SDKP in a classic rat model of vascular-renal hypertension, known as the two-kidney-one-valve model (2K1C). The peptide was administered subcutaneously at a dose of 400 µg/kg/day. Despite sustained elevated blood pressure and heart hypertrophy, significant reductions in the number of inflammatory and proliferating cells in the heart muscle were observed. The proportion of interstitial collagen decreased from approximately 10.1% in hypertensive rats to approximately 5.4%, which is a level almost identical to that in apparently operated animals (approximately 5.3%). This means that tissue remodeling has changed despite the sustained pressure overload, which supports the hypothesis of an independent mechanism beyond the reduction of pressure [8].

In the narrative review, Cavasin and colleagues discussed the complementary properties of thymoquinone β4 and its Ac-SDKP fragment. Thymoquinone β4 is involved in cell migration and survival, while Ac-SDKP exhibits anti-angiogenic activity in hypertension models. In heart attack studies, the peptide limited inflammation, reduced fibrosis, and also promoted angiogenesis, which was observed both in vivo and ex vivo. In mouse models, it also reduced the risk of heart valve rupture. The overlap of the effects suggests that Ac-SDKP may be responsible for some of the biological effects attributed to thymoquinone β4. However, the authors emphasized the need for clinical studies in humans [9].

Ac-SDKP was also studied for its effect on the enzymes that break down extracellular matrix components. In adult rat heart fibroblasts, Rhaleb and colleagues showed that interleukin 1β (IL-1β) significantly increases the expression of MMP-2, MMP-9, and MMP-13 enzymes. These enzymes are involved in the degradation of the matrix and may contribute to the adverse remodeling of tissues. Ac-SDKP did not alter the underlying MMP expression, but it strongly inhibited the growth induced by IL-1β. At the same time, it increased the expression of natural metaloproteinase inhibitors, TIMP-1 and TIMP-2, restoring more balanced regulation of matrix remodeling.

The peptide also limited the activation of NF-κB and ERK/MAPK, two important pathways associated with inflammation and proliferation. Importantly, IL-1β did not increase collagen production in this model, and Ac-SDKP also did not affect its synthesis. This suggests selective regulation of tissue remodeling rather than a general inhibition of collagen production. The results suggest the possible role of Ac-SDKP in maintaining the balance of processes associated with the extracellular matrix [10].

Nakagawa and colleagues studied Ac-SDKP in a mouse model of T-cell-dependent myocardial inflammation. In immunized mice Lewis receiving the peptide, both the contractile and relaxation functions of the heart were preserved. The organ enlargement, fibrous tissue formation, and damage to its structure were also limited. Histological analysis showed a reduced infiltration of immune cells, including macrophages, dendritic cells, and T-cells.

The levels of inflammatory mediators, including IL-1α, TNF-α, IL-2 and IL-17, chemokines CINC-1 and IP-10, adhesion molecules ICAM-1 and L-selectin, and metalloproteinases, also decreased. Ac-SDKP, however, did not change the levels of anti-myosin autoantibodies or the T-cell responses specific to the antigen. This suggests that the observed protective effect resulted primarily from a reduction in the recruitment of immune cells and inflammatory mediators, rather than a change in the production of autoantibodies or the activation of T-cells [11].

González and colleagues studied Ac-SDKP in rats that were given angiotensin II for three weeks. The arterial pressure and heart hypertrophy remained elevated in both treated and control animals. However, Ac-SDKP prevented the increase in total collagen content and its cross-linking. The mechanism involved inhibition of the expression of the oxidative lysosomal deoxyribonuclease (LOX) mRNA and the protein LOXL1, which are enzymes involved in the formation of cross-links between collagen and the stiffening of fibrous tissue.

Additionally, TGF-β expression, NF-κB activation, and influx of CD4⁺ and CD8⁺ T lymphocytes and CD68⁺ macrophages into the myocardium were reduced. The influx of CD4⁺ lymphocytes correlated with the expression of LOXL1, suggesting a mechanistic link between immune cell activity and fibrosis. The results indicate anti-inflammatory and anti-fibrotic effects independent of changes in arterial pressure [12].

Peng and colleagues analyzed the effect of Ac-SDKP on the early and late stages of heart damage after infarction in C57BL/6J mice. The animals received 1.6 mg/kg/day. In the first week, the frequency of fatal heart wall ruptures decreased, ICAM-1 expression, macrophage influx, gelatin degrading enzyme activity, p53 level, and cardiomyocyte death all decreased. At the same time, the number of small blood vessels increased at the edges of the damaged area, suggesting an intensification of angiogenesis.

In the fifth week, a lower content of interstitial collagen was observed, a better preserved heart structure, lower levels of stress-related endoplasmic reticulum stress including CHOP, and maintenance of SERCA2, a protein important for calcium regulation in cardiomyocytes. Overall heart function was more favorable. The study indicates changes in both early damage and subsequent remodeling of the cells [13].

Castoldi and colleagues evaluated Ac-SDKP in a mouse model of diabetic cardiomyopathy. Two months after the onset of diabetes, they began administering the peptide at a dose of 1 mg/kg/day via a minipump. In diabetic mice, hyperglycemia, increased interstitial and perivascular fibrosis, and elevated levels of TGF-β1 and phosphorylated Smad2/3 proteins were observed. Ac-SDKP reduced both types of fibrosis and limited TGF-β/Smad signaling, also in animals receiving ramipril, an ACE inhibitor.

An echocardiographic study showed heart contractility and relaxation disorders associated with diabetes. Insulin and ramipril restored both functions, while Ac-SDKP partially improved relaxation. The results indicate an anti-fibrotic effect, accompanied by a moderate functional improvement in this model [14].

Sharma and colleagues investigated the protection of coronary vessels against radiation-induced damage. In a rat model of thoracic irradiation, Ac-SDKP was administered subcutaneously for 18 weeks. The radiation reduced resting blood flow through the heart, led to endothelial cell death, increased the thickening of the coronary vessels, and disrupted the binding proteins of tight junctions, including claudin-1 and JAM-2.

The Ac-SDKP restored blood flow towards normal levels, promoted endothelial cell maintenance, reduced fibrosis, and improved the organization of tight junctions. Laboratory studies showed that the peptide penetrated endothelial cells and reduced the formation of reactive oxygen species after irradiation. In live animals, the labeled peptide accumulated in endothelial cells within a few hours. The results indicate vascular protection, reduced oxidative damage, and improved microcirculation in this model [15].

In studies on human heart fibroblasts, cells were exposed to Ac-SDKP at a concentration of 10 nM and then to tunicamycin (0.25 µg/ml), which induces endoplasmic reticulum stress. The peptide limited excessive collagen production in stressed cells. This effect was associated with a weakening of the stress response, a reduction in CHOP and NF-κB activity, and a decrease in IL-6 levels.

Following genetic downregulation of CHOP Ac-SDKP, it still limited the activity of NF-κB and the expression of type I collagen at both the protein and mRNA levels. The results support the hypothesis that the peptide can limit excessive production of components of fibrous tissue under conditions of cellular stress [16].

In human coronary endothelial cells, TNF-α stimulation resulted in a significant increase in the expression of ICAM-1, an adhesion molecule involved in the adhesion of leukocytes to the vessel surfaces. Preliminary exposure to Ac-SDKP reduced ICAM-1 levels in a dose-dependent manner. Mechanistic analysis indicated inhibition of the IKK → IκB → NF-κB cascade, which plays a central role in the activation of inflammatory genes. The other two pathways, p38 MAPK and ERK, remained unchanged. This suggests a selective effect of Ac-SDKP on NF-κB signaling in endothelial cells. However, these are cell-based results and do not confirm clinical protection of the vessels [17].

In a mouse model of angiotensin II-induced hypertension, Ac-SDKP reduced collagen deposition in the aorta and reduced the expression of collagen type I and III mRNA. Lower levels of protein kinase C activity were also observed, as was reduced oxidative stress and reduced expression of ICAM-1 and increased macrophage influx into the vessel wall. TGF-β1 and Smad2 activity decreased, while the level of Smad7, a natural inhibitor of this pathway, increased. Arterial pressure and aortic thickness remained elevated, indicating that the observed changes in the vessel wall were not due to a reduction in pressure [18].

In a subsequent mouse model of thoracic irradiation, 18-week administration of Ac-SDKP promoted heart function, reduced extracellular matrix accumulation and fibrosis, reduced macrophage influx, and reduced cardiomyocyte death. Mac-2 (galectin-3) levels and release also decreased. Ac-SDKP was observed within macrophages near the cell nucleus, and its presence limited radiation-induced Mac-2 release. When fibroblasts lacked Mac-2, radiation triggered significantly weaker signals promoting fibrosis. These studies provide preclinical evidence of a reduction in inflammatory and fibrous tissue remodeling after irradiation [19].

Respiratory system studies: scarring of the lungs and inflammatory damage

Comparative lung studies analyzed differences between Ac-SDKP and its precursor, thymozine β4. In laboratory experiments on human lung cells derived from individuals with idiopathic pulmonary fibrosis (IPF), Ac-SDKP limited excessive cell proliferation and reduced the expression of two TGF-β-induced fibrosis markers: α-SMA and collagen.

In a mouse model of bleomycin-induced lung injury, tymozine β4 reduced inflammation and early fibrosis on day 7, but did not prevent fibrosis at later stages, between day 14 and 21. The results suggest that Ac-SDKP may inhibit the basic stages of fibrous tissue formation in cells and potentially exhibit more sustained anti-fibrotic effects than its precursor. However, this hypothesis requires further confirmation [20].

In the studies of ceramide, the role of KIF3A and the β-catenin pathway were analyzed. KIF3A levels were reduced in both patient samples and in the lungs of rats. Restoring KIF3A activity reduced β-catenin signaling and its downstream mediators MRTF-A and SRF, limiting the migration of epithelial cells into myofibroblasts (EMyT), a process associated with fibrosis.

Ac-SDKP increased KIF3A activity and reduced β-catenin/MRTF-A/SRF signaling. When KIF3A expression was artificially restricted, the beneficial effects of Ac-SDKP disappeared. This indicates that KIF3A is an essential component of the investigated anti-fibrotic mechanism [21].

In another study, the combination of Ac-SDKP with vascular endothelial growth factor (VIP) reduced the changes resembling chronic obstructive pulmonary disease (COPD) caused by cigarette smoke in mice. Markers of oxidative damage, including MDA, collagen-related hydroxyproline content, and TGF-β levels decreased. At the same time, the concentrations of inflammatory cytokines TNF-α, IL-1β, and IL-6 decreased, and the activity of superoxide dismutase (SOD) increased. Histological examination showed less inflammation and weaker structural remodeling of the lungs. The combination therefore exhibited antioxidant, anti-inflammatory, and anti-fibrotic effects in the smoke-induced injury model [22, 23].

The Ac-SDKP also showed activity in both the early and later stages of pneumatization caused by bleomycin. In CD-1 mice, administration of 0.6 mg/kg intrathecally, initiated on day 0 or 7, improved survival and reduced weight loss associated with bleomycin. Smaller edema, fewer swollen immune cells, better preserved tissue structure, and less fibrosis were observed in the lungs. Collagen staining and soluble collagen levels decreased. IL-17, TGF-β, and α-SMA levels also decreased, indicating fewer myofibroblasts. The effects occurred with both early and delayed initiation of administration [24].

In a mouse model, ac-SDKP reduced fibrosis by affecting the P-HSP27/SNAI1 pathway. Ac-SDKP increased levels of P-HSP27, SNAI1, α-SMA, and type I and III collagen in the lung tissue. Administration of Ac-SDKP before exposure or after disease onset reduced all of these markers and the number of cells simultaneously positive for P-HSP27 and α-SMA. In healthy control animals, the peptide did not alter the expression of these proteins, suggesting that the observed effects are dependent on the disease state of the tissues [25].

The meta-analysis, which included 18 randomized studies conducted between 2008 and 2021, involved a total of 428 animals. Compared to untreated models, Ac-SDKP reduced several fibrosis markers: α-SMA (standardized mean difference [SMD] −2.44), type I collagen (SMD −5.36), type III collagen (SMD −3.07), TGF-β (SMD −2.88), and the surface area of lung nodules (SMD −1.80). For all these parameters, p < 0.001 was reported.

The hydroxyproline modification, a marker of collagen content (SMD 7.62; 95% CI 4.90–10.33; p < 0.001), was also significant, indicating an effect on collagen metabolism. The combined results of animal studies support the presence of an anti-fibrotic signal in the models analyzed, but are subject to methodological limitations inherent in pre-clinical meta-analyses [26].

In another study, rats were exposed to silica to induce fibrosis, and then Ac-SDKP was administered in a prophylactic regimen or after the development of lesions at a dose of 800 µg/kg/day. Compared to the control groups with silica, the levels of the proteins TGF-β1 and CTGF in the lungs were significantly lower, being approximately 0.244 ± 0.016 and 0.241 ± 0.017, respectively. The levels of the mRNAs, especially CTGF (p < 0.05), also decreased. In the prophylactic group, both the protein and the mRNA levels of TGF-β1 were significantly lower than in the eight-week silica model. Histological studies confirmed the reduced fibrosis [27].

In the next model, the Ac-SDKP reduced the accumulation of collagen and improved the structure of the lungs. The mice were administered the peptide after damage or 48 hours before exposure to the silica. In the therapeutic groups, compared to the silica models, the area of the nodules decreased to 84.28% and 67.93%, the level of hydroxyproline to 70.89% and 58.18%, and the type I collagen to 71.08% and 58.13%, and the type III collagen to 80.13% and 70.70%, corresponding control values at individual time points.

In prophylactic groups, compared to the eight-week silica model, the area of nodules decreased to 61.13%, hydroxyproline to 60.27%, and type I and III collagen to 40.13% and 65.77%, respectively. Immunohistochemical staining with HE and VG showed milder fiberization. The results confirm the reduction in both collagen content and visible fiber changes in the studied model [28].

Studies on silica exposure also included the lungs and bones. In mouse and cell models, silica activated TLR4 and RANKL, exacerbating lung inflammation and the formation of osteoclasts responsible for bone resorption. Ac-SDKP inhibited TLR4 and RANKL signaling, promoted the maintenance of pulmonary elastin, reduced inflammation and macrophage activation. In bone tissue, it inhibited osteoclast differentiation and helped maintain bone density and microarchitecture. The results indicate simultaneous protective changes in the lungs and bone tissue in experimental models of silica-related injury [29].

Ac-SDKP was also studied for its effect on the differentiation of fibroblasts into myofibroblasts. TGF-β1 stimulates lung fibroblasts to undergo this transformation and increases collagen production. When Ac-SDKP was administered before exposure to TGF-β1, levels of α-SMA and collagen decreased, as did levels of TGF-β1 and its receptor.

In rats with pulmonary damage caused by silica, administration of the peptide before or after exposure reduced TGF-β1 levels, RAS signaling and SRF activity, and decreased the number of myofibroblasts positive for α-SMA in the lung nodules. This was accompanied by a reduced deposition of collagen [30, 31].

In studies of epithelial cells of the lung alveoli, the transendothelial migration was analyzed. Under the influence of silica and TGF-β1, the levels of epithelial markers such as E-cadherin and SP-A decreased, while the levels of mesenchymal and fiber markers, including wimentin, α-SMA, and collagen types I and III, increased.

The Ac-SDKP limited these changes. The cells retained more epithelial characteristics, the levels of fiber-forming markers decreased, and the activity of the TGF-β1/ROCK1 pathway was attenuated. This suggests better preservation of the epithelial structure of the pulmonary alveoli under experimental damage conditions [32].

Ac-SDKP also affected the stress of the endoplasmic reticulum and the death of the epithelial cells of the lung alveoli. Exposure to silica increased the levels of GRP78, phosphorylated PERK and eIF2α, CHOP and caspase-12, which was accompanied by the intense death of the cells. In the presence of Ac-SDKP, as with the use of the 4-PBA stress inhibitor, these markers decreased. The death of the cells in laboratory experiments and in rats was also limited, as was the collagen content in the lungs. The results suggest that the impairment of the PERK/eIF2α/CHOP pathway and caspase-12 activity may be involved in protecting the epithelium and limiting fibrosis [33].

Kidney studies: fibrosis and filtration function

Nakagawa and colleagues (2017) demonstrated in a mouse model of NZBWF1 predisposed to congestive heart failure that Ac-SDKP limited kidney damage and renal tubular sclerosis without lowering systolic blood pressure. Severe hypertension, albuminuria, and premature death occurred in treated animals later, but these differences did not reach statistical significance [34].

Worou and colleagues (2015) studied Dahl-sensitive mice that received Ac-SDKP for six weeks at doses of 800 or 1600 µg/kg/day. A high-salt diet still increased arterial pressure, but less inflammation was observed in the kidneys, and the glomeruli were less fibrous and better preserved. Only the higher dose reduced albuminuria in salt-sensitive mice. In a more resistant SS13BN line, both doses prevented albumin loss and structural damage. The results suggest that at least some of the renal effects were independent of the reduction in pressure [35].

Liao and colleagues (2015) studied Ac-SDKP in mice predisposed to gout for 20 weeks. In animals receiving the peptide, improved kidney function was observed, although levels of autoantibodies associated with gout did not change. There were fewer infiltrating macrophages and T lymphocytes in the kidneys. Cytokine and chemokine levels decreased, and the activation of complement components C5–9 and mediators RANTES, MCP-5 and ICAM-1 was limited. This was accompanied by improved filtration function and reduced microscopic damage [36].

In a model of hypertension caused by DOCA and salt, Rhaleb and colleagues (2011) administered Ac-SDKP to mice at a dose of 800 µg/kg/day for 12 weeks. Despite the sustained hypertension, renal fibrosis, matrix deposition in the glomeruli, and influx of monocytes and macrophages were reduced. Albuminuria decreased from 41 ± 5 µg to 13 ± 3 µg per 10 g of body weight per day, reaching values close to the control values. The level of nefrin, an important protein of the filtration barrier, was also partially restored. The results indicate protection of the filtration barrier and reduction of fibrosis regardless of arterial pressure [37].

Shibuya and colleagues (2005) analyzed Ac-SDKP in db/db mice with type 2 diabetes. Eight-week administration using minipumps increased plasma peptide concentrations approximately threefold without changing glycemia. The thickening of the glomeruli, excessive deposition of the mesangial matrix and extracellular matrix components were limited. Plasma creatinine concentrations approached normal values. Albuminuria also decreased, but the difference was not statistically significant. Mechanistically, Ac-SDKP inhibited the movement of Smad3 to the cell nucleus, limiting TGF-β/Smad signaling associated with fibrosis [38].

Castoldi and colleagues (2013) studied rats with diabetes who were given Ac-SDKP at a dose of 1 mg/kg/day, ramipril at a dose of 3 mg/kg/day, both compounds together, or a control treatment. In untreated animals, there was hyperglycemia, increased albuminuria, kidney fibrosis, and decreased nephrin in the glomeruli. Ac-SDKP alone limited fibrosis but did not improve albuminuria. Ramipril reduced both albuminuria and fibrosis and restored the level of nephrin. The combination of Ac-SDKP with ramipril more strongly limited fibrosis than ramipril alone, but did not lead to an additional improvement in albuminuria. The results indicate an additional anti-fibrotic effect in the studied model, without additional improvement in albumin excretion [39].

Zhang and colleagues (2022) developed a biologically inspired dual-network hydrogel composed of gelatin and a curcumin-zinc complex, coated with DOPA and functionalized with immobilized Ac-SDKP. The system was designed to reduce problems related to solubility, absorption, and stability of free substances. After in vivo application in the kidneys of rats after partial nephrectomy, the hydrogel reduced local fibrosis, promoted angiogenesis, and stimulated the formation of new renal capillaries. Material studies confirmed appropriate porosity, mechanical strength, and biocompatibility, which supports further research on this solution [40].

Zuo and colleagues (2013) compared Ac-SDKP, thymozine β4, and thymozine β4 in combination with a prolin oligopeptidase inhibitor (POP) in models of unilateral urethral stricture in wild-type mice and without PAI-1. Ac-SDKP consistently reduced fibrosis in both genotypes. Less collagen and fibronectin were observed, fewer activated myofibroblasts and macrophages, and weaker signaling promoting fibrosis. Comparative studies also indicate distinct and stage-dependent effects of thymozine β4 [41].

Wang and colleagues (2010) demonstrated that Ac-SDKP reduced inflammation and fibrosis in the kidneys caused by vascular obstruction. In rats with unilateral renal artery stenosis, 14 days of administration of the peptide reduced interstitial fibrosis and inflammatory changes observed in histological examination. A smaller influx of ED-1 macrophages was observed, as well as lower levels of MCP-1, NF-κB, α-SMA, and TGF-β1 in the cell and interstitial membranes. MCP-1 and TGF-β1 gene expression also decreased, indicating a reduction in both the recruitment of inflammatory cells and the activation of the extracellular matrix [42].

Liao and colleagues (2010) administered Ac-SDKP at a dose of 800 µg/kg/day to rats after removal of 5/6 of the kidney mass, starting the administration before or after damage occurred. Despite persistent hypertension and left ventricular hypertrophy, the peptide reduced albuminuria, limited the influx of macrophages, and reduced collagen content in the kidneys in both groups. Nephrin loss in the glomeruli was also partially limited or reversed. The results suggest an improvement in the integrity of the filtration barrier both in the early and more advanced stages of damage, mainly through anti-inflammatory and anti-fibrotic effects, rather than pressure control [43].

Peng and colleagues (2001) studied rats after the removal of one kidney; they were given aldosterone and salt for six weeks. The intervention increased arterial pressure, caused an enlargement of the heart and kidneys, and increased the content of collagen and the cell proliferation marker PCNA. Ac-SDKP, especially at a higher dose of 800 µg/kg/day, significantly reduced the content of collagen and PCNA in a dose-dependent manner. However, arterial pressure and organ enlargement remained unchanged, and a lower dose of 400 µg/kg/day produced partial effects [44].

Omata and colleagues (2006) studied rats with kidney inflammation caused by antibodies against the glomerular basement membrane (anti-GBM). Administration of Ac-SDKP at a dose of 1 mg/kg/day was initiated 14 days after onset of the disease and continued for four weeks. Compared with untreated animals, they observed lower urinary protein excretion, lower serum urea and creatinine concentrations, and better creatinine clearance. Tissue studies showed less glomeruli sclerosis and interstitial fibrosis. Fibronectin, collagen, and TGF-β1 levels decreased, while Smad2 signaling increased, while Smad7 increased. The accumulation of macrophages in the renal tissue was also limited [45].

Nagai and colleagues (2014) demonstrated in diabetes models that Ac-SDKP can limit renal fibrosis by inhibiting endothelial-mesenchymal transition (EndMT), the transformation of endothelial cells into cells with pro-fibrotic properties. The peptide restored the activity of natural protective pathways, including let-7 microRNA and FGF receptor signaling, which were impaired by diabetes. Combining Ac-SDKP with an ACE inhibitor provided greater kidney protection than ACE inhibition alone in the model under study [46].

Srivastava and colleagues (2020) compared ACE inhibitors, angiotensin receptor blockers (ARBs), Ac-SDKP, and their combinations in mice with diabetes. The researchers also blocked the natural production of Ac-SDKP using a proline oligopeptidase (POPi) inhibitor. The results suggested that Ac-SDKP participates in the beneficial effects of ACE inhibitors by altering renal metabolism. SIRT3 levels were restored, mitochondrial fatty acid oxidation improved, and abnormal glucose utilization decreased.

The inhibition of the natural formation of Ac-SDKP reduced its concentration, accelerated fibrosis, and disrupted metabolic balance. ACE inhibitors, unlike ARBs, partially restored the peptide level and reduced fibrosis. Both ACE inhibitors and Ac-SDKP limited mesenchymal transits and reduced the content of type I collagen and fibronektin in diabetic kidneys [47].

In clinical studies, Ac-SDKP was also analyzed as a potential agent to protect blood cells during chemotherapy. Carde and colleagues (1992) evaluated Seraspenide in an I–II phase study with a double-blind and alternating design involving 53 patients receiving cytarabine or ifosfamide. Compared with control periods in patients receiving Seraspenide, better preservation of peripheral blood cell counts was observed under conditions of toxic chemotherapy. The drug was well tolerated and no adverse effects were reported. The results encouraged further research into the protection of the hematopoietic system, but did not confirm routine clinical efficacy [48].

In a separate study, no protection against hematological toxicity of chemotherapy was demonstrated. Cappelaere and colleagues (1995) studied 84 patients with advanced squamous cell carcinomas who received carboplatin and continuous infusion of 5-fluorouracil, as well as placebo or Goralatide (Ac-SDKP) at doses of 12.5 or 62.5 µg/kg/day. In 221 cycles of chemotherapy, no differences were observed between the groups in the lowest values of leukocytes, granulocytes, platelets, or hemoglobin. The duration of toxicity also did not change. However, anemia and lymphopenia occurred more frequently in the Goralatide groups. Although the preparation was generally considered to be well tolerated, it did not prevent chemotherapy-related cytopenias and was associated with more frequent anemia and lymphopenia [49].

Nitta and colleagues (2016) studied Ac-SDKP in models of type 1 and type 2 diabetes. CD-1 mice with streptozotocin-induced diabetes and db/db mice received oral Ac-SDKP, imidapryl, an ACE inhibitor, or both compounds. Ac-SDKP and the combined treatment reduced the sclerosis of the glomeruli and the interstitial fibrosis. The cystatin C concentration in the plasma, elevated with renal damage, approached normal values.

All interventions restored levels of anti-fibrotic microRNAs miR-29 and let-7; the greatest improvement was observed in the combination treatment group. The concentration of the peptide in the urine was highest in this same group, indicating greater systemic exposure [50].

Tan and colleagues (2012) gave Ac-SDKP to mice with melanoma MRL/lpr at a dose of 1.0 mg/kg/day for eight weeks. Compared with untreated animals, mice receiving the peptide had lower urinary protein excretion and better kidney function. There were fewer infiltrating T lymphocytes and macrophages in the kidney tissue. NF-κB activation and production of TNF-α and levels of the fibrosis markers TGF-β1, α-SMA and fibronection were reduced. Phosphorylation of Smad2/3 was inhibited, and the level of Smad7 increased.

However, the deposition of immunologic complexes and the level of anti-dsDNA antibodies did not change. This suggests that the effects resulted from limiting the further stages of inflammation and fibrosis, rather than changing antibody formation [51].

Maheshwari and colleagues (2018) studied Zucker rats of normal weight (ZL) and obese (ZO) rats fed a diet with a normal salt content (0.4%) or a high salt content (4%) for eight weeks. One subgroup of ZO rats received Ac-SDKP at a dose of 1.6 mg/kg/day.

A diet rich in salt increased inflammation and fibrosis in both groups, with the highest influx of macrophages in obese rats: 87.8 ± 10.8 vs. 19.14 ± 1.5 cells/mm² in lean rats. Administration of Ac-SDKP reduced the influx of macrophages in obese rats to 32.18 ± 2.4 cells/mm² (p < 0.05) and reduced the sclerosis of the glomeruli and interstitial fibrosis in the renal cortex and medulla (p < 0.05).

The systolic arterial pressure in obese rats fed a diet rich in salt decreased from 164 ± 6.9 to 144.05 ± 14.1 mmHg (p = 0.004). Albuminuria was higher in obese animals than in lean ones, but did not change significantly under the influence of the diet or Ac-SDKP [52].

Neurological studies: models of brain and spinal cord damage

Cellular models and mouse models of Parkinson's disease

Kamarehei and Zahednasab (2025) studied Ac-SDKP in models associated with Parkinson's disease. In cell experiments, preliminary exposure of SH-SY5Y neurons to 20 nM of the peptide limited the damage caused by 6-OHDA, a toxin often used to model Parkinsonian changes.

In studies in rats, daily administration of 800 µg/kg after inducing brain damage with 6-OHDA promoted the preservation of a greater number of dopaminergic neurons and reduced cell death by reducing caspase-3 and caspase-12 activity.

The animals receiving the peptide also showed improved motor coordination, improved spatial memory, and less anxiety-like behaviors and depression.

Mechanistically, the changes were associated with reduced oxidative stress, endoplasmic reticulum stress, and inflammatory signaling in the brain. However, the results pertain to preclinical models and do not confirm the efficacy of Ac-SDKP in patients with Parkinson's disease [53].

Regeneration after spinal cord injury

Hashemizadeh and colleagues (2022) administered Wistar Ac-SDKP subcutaneously to rats at a dose of 0.8 mg/kg once daily for seven days, starting two or six hours after a spinal cord injury caused by a fall from a height.

Compared to untreated animals, the mice receiving the peptide regained better walking ability, lost fewer motor neurons, and showed lower levels of TNF-α and caspase-3.

At the same time, the expression of the CD206 mRNA, a marker associated with M2 macrophages involved in repair processes, increased. Tissue examinations showed less areas of damage.

Overall, a shift in the immune response was observed from the M1 macrophage-related activity towards an M2-type response, which was accompanied by more favorable functional and structural results [54].

Protection after traumatic brain injury (TBI)

Zhang and colleagues (2017) induced controlled brainstem injury in rats, then administered Ac-SDKP at a dose of 0.8 mg/kg/day via a minipump for three days, starting one hour after the injury.

From the 7th to the 35th day, the results of the sensory motor tests were better, and between the 33rd and 35th day, an improvement in spatial learning was also observed compared to the control group (p < 0.05).

At the end of the study, the area of damage to the cortex and the loss of hippocampal neurons were smaller. At the same time, angiogenesis, the formation of new neurons, and the density of dendritic spines increased.

Early administration also limited the deposition of fibrin and the activation of immune cells. Mechanistic studies showed that a significant portion of the anti-inflammatory effect can be explained by the inhibition of TGF-β1/NF-κB signaling [55].

Experimental autoimmune inflammation of the brain and spinal cord (a model resembling multiple sclerosis)

Pejman and colleagues (2020) studied C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE), used as a model for processes resembling multiple sclerosis.

In the EAE, increased levels of endoplasmic reticulum stress markers were observed, including caspase-12, CHOP and PDI, as well as increased oxidative stress and influx of immune cells into the hippocampus.

After administration of Ac-SDKP, caspase-12 and CHOP levels in oligodendrocytes decreased, as did caspase-3 activation. Reactive oxygen species and lipid peroxidation levels also decreased, antioxidant capacity improved, and IL-6 and IL-1β concentrations were lower.

The analysis of brain tissue showed smaller damage to the hippocampus and fewer leaking immune cells, which corresponded to slower progression of disease changes in this model [56].

Additional neurological examinations mentioned in the source material

The bibliography of the source material also included a study of stroke in rats, in which Ac-SDKP was analyzed in combination with the tissue activator plasminogen activator [57], and a study of the thymine β4 fragment regarding hippocampal neurogenesis and spatial memory [58].

The article provided did not present the methods or results of these two studies, therefore no further conclusions regarding their results can be drawn from it.

Liver studies: experimental fibrosis

Reduction of liver fibrosis caused by chemical substances

Wei and colleagues (2022) studied mice with liver damage caused by carbon tetrachloride (CCl₄). After using Ac-SDKP, they observed less death of astrocytes, the main cells involved in the formation of fibrous tissue in the liver, and less fibrosis.

Mechanistic studies showed that the peptide reduced the level of WTAP, a protein involved in the addition of m⁶A modifications to RNA. This change stabilized the Ptch1 RNA and affected the activity of the Hedgehog pathway, an important regulator of processes related to fiberization.

The results indicate an anti-angiogenic mechanism associated with the WTAP/m⁶A/Ptch1 pathway and Hedgehog signaling regulation [59].

Protection in the model of fibrosis caused by biliary tract obstruction

Zhang and colleagues (2012) used a rat model of biliary duct ligation (BDL) and then administered Ac-SDKP for two weeks.

Compared to untreated animals, a weakening of TGF-β1 signaling and lower levels of marker molecules activated by astrocytes were observed, including α-SMA and FSP-1.

The expression of genes related to type I and III collagen and enzymes involved in matrix remodeling, such as MMP-2, TIMP-1 and TIMP-2, also decreased.

Blood parameters related to liver function improved: ALT, AST, bilirubin and prothrombin time approached normal values. Histological examinations showed fewer fat cells, less deposition of collagen and weaker fibrosis and inflammation [60].

Maintenance of natural protective and repair mechanisms

Chen and colleagues (2010) showed that during prolonged exposure to CCl₄, the natural concentrations of Ac-SDKP gradually decreased.

Administering the peptide by infusion at a dose of 800 µg/kg/day for eight weeks helped maintain its baseline level and reduced liver damage, inflammation, and fibrosis.

The activity of hepatic enzymes in the blood decreased, the number of inflammatory CD45⁺ cells decreased, and the amount of collagen and α-SMA deposits also decreased. TGF-β1 and phosphorylated Smad2/3 levels also decreased, while the activity of signaling molecules related to tissue repair, such as BMP-7 and phosphorylated Smad1/5/8, increased.

In cell experiments, Ac-SDKP directly inhibited the activation of astrocytes, which confirmed the anti-fibrotic effect at the cellular level [61].

Skin regeneration, wound healing models and other experimental results

Hydrogel containing Ac-SDKP and scar reconstruction

A special tissue adhesive based on cellulose, Dopa-OCMC-PAA, was developed, which is compared with OCMC-PAA and is intended for the transfer and release of Ac-SDKP.

Both versions showed appropriate swelling and degradation properties, good mechanical strength, and cell compatibility, but Dopa-OCMC-PAA achieved better results.

In mice with liver bleeding, this glue slowed down the bleeding faster. In fibroblast tests, it increased the levels of enzymes involved in tissue remodeling, MMP-1 and MMP-3, while at the same time reducing the activity of genes related to collagen.

In rabbits with hypertrophic ear wounds, the combination of Dopa-OCMC-PAA with Ac-SDKP reduced the severity of scarring, decreased the number of cells, and improved collagen organization. MMP-1 and MMP-3 levels were also increased, and collagen genes were less active. The results indicated better wound healing and less scarring in the models [62].

Local application and skin survival and repair processes

In rat models of surgical skin flaps, abdominal and dorsal flaps, administration of Ac-SDKP in injections at a dose of 5 µg/kg twice daily for three days increased the surface area of live skin.

In the abdominal pleurae, the proportion of living tissue increased from 50.9 ± 19.3% to 66.4 ± 7.5%, and in the thoracic pleurae from 53.4 ± 4.2% to 74.7 ± 6.6%.

In skin tissue damaged by UVB radiation, topical application of the peptide improved cell survival. Superficial administration also accelerated the formation of new epidermis, increased the level of keratins-14, a marker of cells involved in skin repair, and fibronektin. The results indicate a role in the processes of angiogenesis and tissue repair under experimental conditions [63].

Protection of hematopoietic function during chemotherapy

In a study of mice receiving docsorubicine, a chemotherapeutic drug, administration of Ac-SDKP at 2.4 µg/day, continuously or in divided doses, initiated 48 hours before treatment, reduced mortality and protected hematopoietic stem cells.

Protection was observed in measurements of LTRC, CFU-S, HPP-CFC and CFU-GM. The addition of G-CSF additionally increased the recovery of CFU-GM.

The moment of initiation of the infusion was crucial. Initiation before chemotherapy was necessary to limit both the short-term damage to the bone marrow and the long-term loss of stem cells in this model [64].

Stronger anti-fibrotic activity of modified analogues and combinations with ACE inhibitors

In experiments on pulmonary fibroblasts, the form of Ac-SDKP that is resistant to degradation by ACE more strongly restricted the signaling of TGF-β/Smad3 and collagen deposition than the natural molecule.

The truncated fragment of Ac-DKP showed only weak effects and was slowly degraded by ACE.

The combination of the peptide with ACE inhibitors more strongly reduced the level of hydroxyproline, a marker of collagen content, than the peptide itself. The results suggest the possibility of further studies on modified analogues and their interactions.

At concentrations ranging from 10⁻⁶ to 10⁻¹⁷ M, both thymozine β4 and Ac-SDKP reduced the proliferation of fat cells, with the strongest effect being observed at 10⁻¹⁴ M. They also caused atypical changes in the nuclei of the cells associated with the arrest of the cell cycle.

At a concentration of 10⁻⁸ M, both peptides also induced the degranulation of fat cells. Ac-SDKP showed a stronger effect, approximately 89%, than thymozine β4, approximately 57%. The remaining fragments of thymozine β4 showed no activity, suggesting that these responses are dependent on the intact peptides being studied rather than on other fragments [65, 66].

Experimental doses of Ac-SDKP in published studies – not recommended for humans

The following values describe the protocols used in the cited animal and cell experiments. They are not fixed doses for humans.

In the pre-clinical studies analyzed, Ac-SDKP was often administered subcutaneously using minipumps at a dose of approximately 0.8 mg/kg/day to assess fibrosis and inflammation in the heart, vessels, and kidneys. In mouse models of heart attack, 1.6 mg/kg/day was sometimes used in early tissue protection studies.

In experiments involving the brain and the nervous system, short cycles initiated within a few hours of injury typically included approximately 0.8 mg/kg/day for three to seven days. In cellular studies, an initial exposure of approximately 10 nM of the peptide was often used.

In models of chronic liver injury, anti-fibrotic protocols often included approximately 0.8 mg/kg/day. In the model of pulmonary fibrosis caused by bleomycin, 0.6 mg/kg intrathecally was administered with repeated administrations starting on day 0 or 7.

In studies of skin healing and wounds, topical regimens included 5 µg/kg per injection twice daily for three days or hydrogels containing a peptide and releasing it locally.

Very small amounts were used in hematological and bone marrow protection studies, for example 2.4 µg/day in mice before chemotherapy and short cycles of µg/kg/day in early clinical studies.

Interpretation of the results and limitations of the available evidence

The majority of the literature presented includes cellular experiments and animal models. Changes in collagen deposition, inflammatory mediators, tissue structure, and experimental functional parameters do not in themselves constitute evidence of therapeutic efficacy in humans.

The early clinical studies cited mainly concerned hematological parameters during chemotherapy and yielded ambiguous results, including negative results from a randomized study [48, 49].

Experimental routes of administration, amounts of substances, and exposure periods should be treated as elements of the research methodology, and not as recommendations for individual use.

Editorial note: This article is for educational and scientific purposes only. It presents the results of research on Ac-SDKP, molecular mechanisms, and limitations of the available evidence. It does not constitute medical advice, does not recommend the use of Ac-SDKP, nor specifies dosage, administration, or treatment protocols. The results of laboratory studies and animal experiments do not confirm the safety or efficacy of Ac-SDKP in humans.

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