IL-22 attenuates MAFLD progression by modulating oxidative stress and ferroptosis

Metabolic-associated fatty liver disease (MAFLD) is a common liver disease in clinical practice and currently has limited standardized medications or treatments. The study aimed to evaluate the therapeutic effects of interleukin-22 (IL-22) on metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, and to explore its underlying molecular mechanisms. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 12 weeks and treated with different doses of IL-22 intraperitoneally. IL-22 treatment significantly reduced hepatic lipid accumulation, suppressed hepatic stellate cell (HSC) activation, and prevented liver fibrosis. It also attenuated oxidative stress, evidenced by elevated SOD levels and reduced ROS, MDA levels. Meanwhile, changes in mitochondria morphology, along with alterations in GSH and Fe²⁺ levels, further indicated that IL-22 may inhibit ferroptosis in the MASH liver. Further investigation revealed that IL-22 facilitated the translocation of Nrf2 into the nucleus, downregulated Keap1 expression, and upregulated Hmox1, Gpx4, and Slc7a11 expression. Moreover, IL-22 treatment significantly reduced lipid accumulation in free fatty acid (FFA)-induced AML-12 cells. Mechanistic experiments demonstrated that IL-22 can activate the Nrf2/Gpx4/Slc7a11 signaling pathway and inhibit oxidative stress and ferroptosis in AML-12 cells. These effects were significantly diminished by the Nrf2 inhibitor ML385. In brief, IL-22 mitigated the progression of MASH by modulating hepatic oxidative stress and ferroptosis. Therefore, IL-22 may represent a potential option for treating MASH.