Resveratrol attenuates Cr(VI)-induced ferroptosis through SIRT3 activation in nephrocytes and in vivo.

Hexavalent chromium [Cr(VI)], a widespread environmental toxicant with mutagenic and carcinogenic potential, preferentially accumulates in the kidneys, though its nephrotoxic mechanisms remain incompletely understood. This study demonstrates that Cr(VI) induces ferroptosis, an iron-dependent regulated cell death, in nephrocytes. Cr(VI) exposure resulted in mitochondrial dysfunction, iron overload, depleted glutathione (GSH) and superoxide dismutase (SOD), and elevated malondialdehyde (MDA) and reactive oxygen species (ROS). These changes were accompanied by downregulation of the ferroptosis-related proteins GPX4 and FTH1, upregulation of ACSL4, and reduced cell viability. We further identified the mitochondrial deacetylase SIRT3 as a key negative regulator of this process. Genetic inhibition of SIRT3 exacerbated Cr(VI)-induced ferroptosis. Resveratrol is predicted to directly interact with SIRT3 via molecular docking, and functional cellular/in vivo assays confirm resveratrol triggers SIRT3 upregulation and improves its functional activity, thereby alleviating ferroptotic damage by restoring redox and iron homeostasis. The protective effect of resveratrol was largely abolished upon SIRT3 inhibition, indicating a SIRT3-dependent mechanism. Consistent with cellular findings, resveratrol administration in a murine model of Cr(VI) nephrotoxicity attenuated renal tissue injury, upregulated SIRT3 and GPX4 expression, and mitigated pathological changes. Our results reveal a novel SIRT3-mediated pathway through which resveratrol counteracts Cr(VI)-induced renal ferroptosis, highlighting its potential as a therapeutic agent against heavy metal-induced kidney damage.