Metformin Partially Modulates Cisplatin-Induced Neuronal Senescence but Does Not Prevent Rat Peripheral Sensory Hypersensitivity

Therapy-induced senescence (TIS) is recognized as a contributor to chemotherapy-associated adverse effects, including neurotoxicity. While senolytics have shown promise in alleviating chemotherapy-induced peripheral neuropathy (CIPN), their clinical translation might be hindered by unfavorable safety profiles, shifting interest toward less toxic senomorphics. We investigated the senomorphic potential of metformin (Met) in counteracting cisplatin (Cis)-induced senescence using both an in vitro model of human induced pluripotent stem cell-derived motor neurons (iPSC-MNs) and an in vivo rat model of CIPN. Exposure of iPSC-MNs to Cis induced hallmark features of senescence, including increased senescence-associated β-galactosidase (SA-β-gal) activity and upregulation of senescence-associated markers, as confirmed by immunofluorescence (increased p16INK4a and decreased Lamin B1) and qPCR (CDKN2A, CDKN1A, CXCL8 upregulation) analyses. While Met did not significantly reduce SA-β-gal activity or restore cell viability, it attenuated the expression of key senescence-associated transcripts, including CDKN2A and components of the senescence-associated secretory phenotype (SASP) such as CXCL8, indicating partial senomorphic activity. In vivo, Cis administered in two cycles (cumulative dose: 23 mg/kg) elicited mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Analysis of dorsal root ganglia (DRG) on day 8 post-treatment revealed strong SA-β-gal staining and increased expression of cdkn1a, cdkn2a, and SASP mediators (Il6). Met pre-treatment reversed the upregulation of cdkn1a, cdkn2a, and Il6, but did not alleviate the sensory deficits induced by Cis. Our findings support the senomorphic activity of Met both in vitro and in vivo yet demonstrate its limited efficacy in functionally mitigating CIPN.