mTOR-Mediated Autophagy Regulates Cadmium-Induced Kidney Injury via Pyroptosis

Cadmium (Cd), a toxic heavy metal, negatively impacts global livestock production primarily by contaminating feed ingredients and through secondary contamination during feed processing. Beyond its economic consequences, Cd also poses a serious risk to food safety and human health. The NLRP3 (nucleotide-binding oligomerization domain-like pyrin-domain-containing protein 3) inflammasome is a central regulator of pyroptosis, a form of programmed cell death implicated in kidney injury. Additionally, autophagy is known to play a role in renal inflammation. The mammalian target of rapamycin (mTOR) is a critical modulator of both pyroptosis and autophagy; however, its role in Cd-induced kidney injury remains poorly defined.
In this study, we investigated the involvement of mTOR-regulated autophagy and pyroptosis in Cd-induced renal damage and explored the underlying molecular mechanisms. Our results showed that Cd exposure compromised kidney cell membrane integrity, upregulated pyroptosis-related proteins, and increased the release of pro-inflammatory cytokines. Treatment with CY-09, an NLRP3 inhibitor, significantly reduced pyroptosis following Cd exposure. Furthermore, Cd exposure was found to enhance autophagic activity in renal cells.
Importantly, both in vivo and in vitro administration of rapamycin, an mTOR inhibitor, suppressed the expression of pyroptosis-associated proteins and markedly alleviated Cd-induced kidney injury. Collectively, these findings suggest that mTOR-mediated autophagy exerts a protective effect against NLRP3 inflammasome-driven kidney damage caused by Cd exposure, offering novel insights into potential therapeutic strategies for Cd poisoning.