D-Pinitol Mitigates Renal Senescence via Targeting the SARM1-cGAS-STING Signaling Axis to Restore Mitochondrial Function and Dampen Inflammatory Responses

Background: Renal aging represents a pivotal contributor to the pathogenesis and progression of age-related kidney disorders. D-Pinitol (DP), a bioactive cyclitol naturally present in food plants, exhibits multiple beneficial biological activities. Nevertheless, its role in counteracting renal aging remains unclear. Methods: This study employed both in vitro (HK-2 cells) and in vivo (C57BL/6J mice) models of D-galactose (DG)-induced renal aging. A panel of experimental approaches was applied to characterize the protective effects and molecular mechanisms of DP against renal aging, including Western blot, qPCR, ELISA, transcriptomic profiling, transmission electron microscopy, surface plasmon resonance (SPR), immunohistochemistry, and immunofluorescence staining. Results: DP significantly attenuated DG-induced renal aging-like changes in vitro and in vivo by preserving mitochondrial function and alleviating inflammatory responses. Transcriptomic analysis suggested SARM1 as a potential key target responsible for the beneficial effects of DP. In DG-induced aging models, SARM1 was remarkably upregulated in a tubule-specific pattern and acted as a critical mediator of mitochondrial dysfunction. Damaged mitochondria released mtDNA, which further activated the cGAS–STING innate immune signaling pathway, consequently promoting the senescence-associated secretory phenotype (SASP) and renal inflammation. Mechanistically, molecular docking and related assays suggested that DP may stabilize the auto-inhibitory conformation of SARM1, thereby potentially preventing its activation. Conclusions: DP attenuates DG-induced renal aging-like changes via suppressing the SARM1–cGAS–STING axis, thereby restoring mitochondrial homeostasis and mitigating inflammation. Given the lack of effective interventions targeting renal aging, these findings suggest SARM1 as a novel potential therapeutic target for renal aging and highlight DP as a promising food-derived anti-aging ingredient for renal protection.