ARHGAP10-G0S2 interaction attenuates phenotypic switching of corpus cavernosum smooth muscle cells by restoring mitochondrial function, thereby ameliorating erectile dysfunction in diabetic rats

Diabetes mellitus erectile dysfunction (DMED) is a common and severe complication, posing a major clinical challenge due to its complex pathogenesis and limited therapeutic options. Emerging evidence indicates that the phenotypic switching of corpus cavernosum smooth muscle cells (CCSMCs) from a contractile to a synthetic state is a key event in DMED progression. However, the regulatory mechanisms linking diabetes-associated oxidative stress to this process remain elusive. This study aimed to investigate the role of ARHGAP10 in the phenotypic switching of CCSMCs under diabetic conditions and its associated mechanisms involving mitochondrial dysfunction. In the streptozotocin-induced DMED rat model, intracavernosal injections of Arhgap10 - or G0s2 -overexpressing adenoviruses were performed to evaluate their effects on erectile function. In primary CCSMCs, we conducted RNA sequencing and co-immunoprecipitation assays. Additionally, mitochondrial function was comprehensively assessed by measuring membrane potential, reactive oxygen species (ROS) production, and ultrastructural morphology. ARHGAP10 expression was significantly downregulated in the corpus cavernosum of diabetic rats. Its restoration improved erectile function and suppressed the synthetic phenotypic switching in CCSMCs. Mechanistically, transcriptomics analysis identified G0s2 as a key downstream effector. Moreover, we demonstrated that ARHGAP10 interacted with G0S2, and this interaction was essential for mitigating mitochondrial dysfunction by restoring membrane potential, reducing mitochondrial ROS overproduction, and improving ultrastructure. Importantly, G0s2 knockdown abolished the protective effects of ARHGAP10 on the contractile phenotype in vitro. Furthermore, in vivo overexpression of G0s2 alone effectively phenocopied the therapeutic benefits of ARHGAP10, restoring erectile function and preserving the contractile phenotype. Our study reveals that the ARHGAP10-G0S2 axis maintains mitochondrial function to preserve CCSMC contractility in DMED, establishing G0S2 as a necessary and sufficient downstream mediator, and thus proposes a novel therapeutic target for this condition.