Ac‐ SDKP modulates apoptosis via HSP27 and the FAS / FASL and mitochondrial axes

BACKGROUND: Silicosis is a progressive, irreversible fibrotic lung disease caused by long-term exposure to crystalline silica. Although the anti-fibrotic tetrapeptide Ac-SDKP has shown promise in reducing fibrosis, the specific molecular mechanisms through which it modulates apoptosis in silica-induced lung injury remain unclear, particularly the role of heat shock protein 27 (HSP27). METHODS: Wistar rats were divided into groups including control, model (2-week, 3-week, and 4-week), and Ac-SDKP prevention/treatment groups. In vitro, MEF and A549 cells were treated with TGF-β1 and Ac-SDKP to observe the effects on apoptosis-related proteins. Additionally, HSP27 interference vectors were constructed to study its role in regulating apoptosis via FAS/FASL and mitochondrial pathways in both in vivo and in vitro models. RESULTS: In vivo, Ac-SDKP administration alleviated silica-induced pulmonary fibrosis and reduced apoptosis in lung tissue. In contrast, in vitro, TGF-β1 stimulation suppressed apoptosis in A549 and MEF cells, whereas Ac-SDKP restored apoptotic activity by regulating the HSP27-mediated FAS/FASL and mitochondrial pathways. Moreover, AAV9-mediated knockdown of HSP27 in mice enhanced apoptosis and attenuated fibrosis, confirming the anti-apoptotic role of HSP27 in silicosis. CONCLUSION: These findings reveal that Ac-SDKP exerts context-dependent modulation of apoptosis through HSP27-protecting acutely injured alveolar epithelial cells in vivo while reinstating apoptotic signaling in EMT-adapted A549 and MEF cells in vitro. Thus, targeting HSP27 may offer a promising therapeutic strategy to restore apoptotic-fibrotic equilibrium in silicosis and related pulmonary fibrotic disorders.