Remodeling lipid and mitochondrial homeostasis: a novel mechanism by which polydatin attenuates renal tubular senescence in chronic kidney disease.

Tubular cell senescence is a well-recognized key driver of chronic kidney disease (CKD) pathogenesis, which imposes a substantial global health burden. Polydatin (PD) is a natural polyphenol derived from Polygonum cuspidatum, its novel potential to modulate tubular cell senescence in CKD-specifically through remodeling lipid dysfunction and restoring mitochondrial homeostasis-remains unelucidated. Our study focused on unraveling the core molecular mechanisms underlying PD driven therapeutic effects in CKD, with SIRT3 as a key target validated by tubule-specific depletion strategies in vivo. PD treatment significantly ameliorates renal dysfunction, attenuates tubular injury, and mitigates interstitial fibrosis in CKD, with consistent renoprotective effects confirmed in vitro. Transcriptomic analyses identified lipid metabolism remodeling and mitochondrial homeostasis restoration as core pathways regulated by PD, with the SIRT3/SOD2 axis emerging as a central regulatory hub. Mechanistically, PD restores SIRT3 expression, which in turn enhances SOD2 deacetylation, boosts antioxidant capacity, reverses lipid dysfunction, and ultimately reduces mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial damage. Notably, PD effectively suppresses the DNA damage response via reducing γH2AX foci formation, thereby alleviating tubular cell senescence (evidenced by decreased p21 expression and SA-β-gal activity in vivo and in vitro). Critically, tubule-specific SIRT3 knockout or siRNA-mediated knockdown abrogated protective effects modulated by PD, underscoring SIRT3 as an essential mediator of its therapeutic actions. Collectively, our study unveils that PD rewires lipid metabolism, restores mitochondrial homeostasis, and activates the SIRT3/SOD2 axis to mitigate DNA damage and suppress tubular senescence, thereby halting CKD progression. These findings position PD as a promising therapeutic candidate for senescence-associated kidney diseases.