Astragaloside IV Mitigates Tacrolimus-Induced Chronic Nephrotoxicity by Regulating the mTOR-TFEB-GADD45α Pathway.

Tacrolimus-induced chronic nephrotoxicity (TICN) limits its clinical application without prevention strategies. Identifying a specific target and finding corresponding drug are critical for its prevention. We previously found that transcription factor EB (TFEB), a substrate of calcineurin, is key to TICN. Further exploration of drugs targeting TFEB without compromising tacrolimus efficacy holds promise for preventing TICN. Astragaloside IV (AS-IV), the major bioactive component of Astragali Radix, can alleviate various renal diseases. However, its regulatory effect on TFEB and the underlying mechanism remain unknown. Herein, we found that AS-IV significantly reactivated TFEB and restored tacrolimus-impaired renal function and pathology, autophagy flux and DNA repair. These effects were reversed upon TFEB knockdown. Further studies revealed that AS-IV did not affect calcineurin but activated TFEB by inhibiting mTOR, which dominantly phosphorylated TFEB Ser211. Altogether, this study suggested that AS-IV mitigated TICN via mTOR-TFEB without affecting calcineurin, making it a promising therapeutic agent for TICN.