The AMPK/ULK1/autophagy pathway: FGF23’s weapon against GSDME-mediated pyroptosis in folic acid-induced acute kidney injury

Résumé fourni par la source

Acute kidney injury (AKI) is a common critical illness in clinical settings. Fibroblast growth factor 23 (FGF23) levels increase rapidly after AKI; however, the role of FGF23 in AKI remains unclear. We investigated the function and underlying mechanisms of FGF23 in patients with AKI and in folic acid (FA)-induced AKI models. FGF23 expression was significantly elevated in AKI patients as well as in both in vivo and in vitro FA-AKI models. GSDME-mediated pyroptosis occurred in renal tubular epithelial cells, with upregulated autophagy marker LC3B-II. Recombinant human FGF23 pretreatment activated the AMPK/ULK1 pathway, increased LC3B-II levels, and inhibited caspase-3/GSDME-mediated pyroptosis in HK-2 cells. Conversely, inhibition of FGF receptors suppressed AMPK/ULK1 activation and autophagy, thereby enhancing pyroptosis. In summary, FGF23 promots autophagy via the AMPK/ULK1 pathway and consequently inhibits caspase-3/GSDME-mediated pyroptosis in FA-AKI. Our findings reveal a novel protective role of FGF23 in AKI, clarify its underlying mechanism, and provide a theoretical foundation for the development of new AKI diagnostic and therapeutic approaches based on FGF23. • FGF23 is markedly upregulated in folic acid–induced AKI models and exerts protective effect on renal tubular epithelial cells. • FGF23 activates AMPK/ULK1-dependent autophagy, suppresses GSDME-mediated pyroptosis, and thereby mitigates tubular injury. • These findings clarify the key protective mechanisms of FGF23 in AKI and provide a theoretical basis for developing novel diagnostic and therapeutic strategies.

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