A new target for curcumin in the treatment of non-alcoholic fatty liver disease: the FTO protein.

Non-alcoholic fatty liver disease (NAFLD) is a significant public health issue with complex pathomechanisms. Curcumin (CUR), a natural polyphenolic compound, is known to regulate lipid metabolism and exert anti-inflammatory effects; however, its specific molecular targets have not been fully elucidated. Therefore, the present study aimed to investigate whether curcumin ameliorates NAFLD by targeting the regulation of fat mass and obesity-associated (FTO) proteins and to elucidate its molecular mechanism for the first time. Six-week-old male C57BL/6 mice were randomly divided into three groups: control (CON, n = 9), high-fat diet (HFD, n = 9), and high-fat diet plus curcumin (HFD + CUR, n = 6) groups. After eight weeks of high-fat diet induction, the HFD + CUR group received curcumin gavages for four weeks. The results showed that the curcumin intervention significantly attenuated hepatic lipid deposition and inhibited FTO protein expression. In vitro models of HepG2 and THLE-2 cells induced by free fatty acids (FFA) further confirmed this effect. Molecular docking and cellular thermal shift assays revealed that FTO is a potential target of curcumin. Mechanistically, curcumin significantly enhanced m6A methylation of PPARα mRNA by inhibiting FTO, thereby activating the PPARα/CPT1α signaling pathway, reducing lipid accumulation, and slowing the progression of NAFLD. In conclusion, we revealed for the first time that curcumin alleviates hepatic cell lipid accumulation by regulating the PPARα/CPT1α signaling pathway through FTO.