Allium polyrhizum Turcz. flavonoids extract alleviates cadmium-induced renal injury through differential regulation of autophagy mediated by mTORC1 and mTORC2.

Cadmium (Cd)-induced nephrotoxicity remains a global health challenge, with dysregulated mechanistic target of rapamycin kinase (mTOR) signaling implicated in its pathogenesis. Allium polyrhizum Turcz. flavonoids (APTF), a traditional Mongolian medicinal plant extract, exhibits potent antioxidant and anti-inflammatory properties, but its protective effects against Cd nephrotoxicity via mTOR pathway modulation have not been evaluated. This study investigated the protective role of APTF against Cd-induced kidney injury, focusing on its dual regulation of mTOR complex (mTORC)1 and mTORC2 pathways. Using in vitro and in vivo Cd exposure models, molecular, biochemical, and computational approaches were used to examine the effects of APTF on mTOR-mediated autophagy pathways. Cd exposure aberrantly activated both mTORC1 and mTORC2, leading to impaired autophagy. mTORC1 inhibited Transcription Factor EB (TFEB)-mediated lysosomal biogenesis and acidification, while mTORC2 disrupted Forkhead box O1 (FOXO1)-RAB7-dependent autophagosome-lysosome fusion. APTF treatment uniquely and simultaneously normalized both pathways: it inhibited mTORC1 to promote TFEB nuclear translocation and lysosomal restoration, and suppressed mTORC2 to enhance FOXO1 activity and RAB7 expression, thereby rescuing autophagic flux. This coordinated action correlated with attenuated oxidative stress, improved gut-kidney axis function, and significant alleviation of renal histological damage and dysfunction. APTF orchestrates a dual-pathway protective mechanism by differentially targeting mTORC1 and mTORC2 to restore coordinated autophagy, highlighting its potential as a novel multi-targeted phytotherapeutic agent against Cd-induced nephrotoxicity.