Source: europepmc · Yan R, Zhe Z, Zhang J, Lin T, Xiao S, Liu H, Mao H, Cooper T, Alqadhi S, Li B, Wu L. · Research Square · 2026-05-25
URL: https://europepmc.org/article/PPR/PPR1238013
AI rationale (4/5, tier: preliminary): Directly addresses mitophagy (PINK1/Parkin pathway implicit) and ROS signalling in nerve repair; rat model with mechanistic focus on mitochondrial homeostasis.
<title>Abstract</title> <p> <bold>Background</bold> : Peripheral nerve injuries cause major functional deficits and have few pharmacological options. We evaluated whether hirudin promotes peripheral nerve repair by enhancing mitophagy, preserving mitochondrial homeostasis, and restraining NLRP3 inflammasome–related pyroptosis. <bold>Methods</bold> : Rat sciatic nerve crush injury was used to assess functional and histological recovery following systemic hirudin administration. In RSC96 Schwann cells, mitochondrial membrane potential, mitochondrial reactive oxygen species, mitophagy markers, and inflammasome activation were evaluated following a standard inflammasome activation paradigm induced by lipopolysaccharide and nigericin. The autophagy inhibitor 3-methyladenine and the selective NLRP3 inhibitor MCC950 were used to interrogate mechanistic pathways. Statistical analysis used t‑tests or one‑way ANOVA with Tukey’s post hoc test. <bold>Results</bold> : Network pharmacology suggested multiple enriched pathways, including the NOD‑like receptor pathway, and prioritized GSDMD and interleukin‑1β as candidates. In vitro, hirudin preserved mitochondrial membrane potential, reduced mitochondrial reactive oxygen species, increased mitophagy markers, and was associated with lower NLRP3/caspase‑1/GSDMD activation. In vivo, hirudin improved sciatic functional index, mitigated gastrocnemius atrophy, and increased markers consistent with axonal regeneration, myelin presence, and vascular remodeling. Co‑treatment with 3‑methyladenine attenuated these effects, whereas MCC950 showed a similar anti‑inflammatory profile. <bold>Conclusions</bold> : These results demonstrate that hirudin promotes peripheral nerve regeneration and functional recovery largely by enhancing mitophagy, preserving mitochondrial homeostasis, and restraining NLRP3 inflammasome activation and pyroptosis. This study highlights the therapeutic potential of hirudin as a multi-target modulator in peripheral nerve injury repair. Specific pathway assignments and cellular sources are interpreted cautiously, and further validation in vivo is warranted. <bold>Trial registration:</bold> Not applicable. </p>