摘要Alcohol-associated liver disease(ALD)remains a predominant cause of chronic hepatic pathology,and effective therapeutic strategies are needed.Krüppel-like factor 15(KLF15)is a member of the KLF family of zinc-finger transcription factors and is ubiquitously expressed in metabolically active tissues,with a particularly high abundance in the liver.KLF15 has been implicated in various hepatic disorders.In this study,we investigated the pathophysiological role of KLF15 in ALD.We established a National Institute on Alcohol Abuse and Alcoholism(NIAAA)model in mice by feeding them an ethanol Lieber-DeCarli liquid diet containing 5％(vol/vol)ethanol for 10 days.EtOH-fed mice were administered binge ethanol gavage(5g/kg,body weight)on D11.We observed that the expression levels of KLF15 were significantly decreased in the livers of ALD patients and model mice.Overexpression of KLF15 conferred substantial protective effects in EtOH-fed mice,as evidenced by attenuated hepatic injury,apoptosis,steatosis and inflammation.In ethanol-treated AML-12 cells,overexpression of KLF15 reduced apoptosis and steatosis,whereas KLF15 knockdown exacerbated these pathological features.By performing RNA-seq and bioinformatics analyses,we observed that KLF15 regulated the AKT pathway by directly binding to the PFKFB3 promoter(-128 to-121).The physical interaction between PFKFB3 and AKT1 was further verified by Co-IP and molecular docking.These results suggest that KLF15 is a pivotal regulator of ALD pathogenesis through modulation of the PFKFB3/AKT axis,highlighting its potential as a novel therapeutic target for ALD intervention.