Impact of chronic social stress on molecular markers of skin regeneration during experimental excisional wounding.

BACKGROUND: The second decade of the 21st century has seen increased environmental stressors, global pandemics, and armed conflicts, all contributing to heightened population morbidity and mortality. Among the affected health outcomes, wound healing has emerged as a critical physiological process vulnerable to impairment by psycho-emotional and social stress. Chronic stress is known to delay tissue repair, disrupt inflammatory responses, and exacerbate oxidative damage, yet the molecular mechanisms linking social stress to impaired skin regeneration remain insufficiently understood. METHODS: This study investigated the impact of chronic social stress (CSS) on molecular pathways involved in apoptosis, cytoprotection, and proliferation during skin wound healing in a rat model. A total of 120 male Wistar rats were allocated into experimental (CSS-exposed), aggressor, and control groups based on behavioral assessments. CSS was induced by combining social isolation and continuous exposure to aggressive conspecifics for 21 days. Full-thickness excisional wounds were created, and skin samples were collected during wounding and at days 1, 3, 7, 14, and 30 post-injury to correspond with the inflammatory, proliferative, and remodeling phases of healing. Immunohistochemical analyses were performed to assess the expression of key markers: HIF1α, BCL2, caspase-3, caspase-9, NRF2, SOX2, PDGFRB, CGRP, p62, and LC3BB. RESULTS: Chronic social stress significantly delayed wound closure and altered the expression of molecular markers critical for tissue regeneration. Immunohistochemical analysis revealed reduced expression of cytoprotective (NRF2, HIF1α) and regenerative (PDGFRB, CGRP) markers, alongside increased markers of apoptosis (caspase-3, caspase-9) and impaired autophagy (p62, LC3BB) in periwound of CSS-exposed rats tissues compared to controls. These molecular alterations corresponded with delayed progression through the inflammatory and proliferative phases and incomplete remodeling at day 30. CONCLUSION: The findings demonstrate that chronic social stress impairs skin wound healing by disrupting the balance of apoptosis, cytoprotection, and proliferation at the molecular level. Suppression of pro-inflammatory and regenerative pathways, combined with enhanced oxidative stress and apoptosis, underlies the observed delays in tissue repair. These results highlight the importance of addressing psycho-social factors in the management of wound healing and suggest potential molecular targets for therapeutic intervention in stress-impaired tissue regeneration.