IntroductionMetabolic dysfunction-associated fatty liver disease (MAFLD), previously known as nonalcoholic fatty liver disease, has become the most prevalent chronic liver disease, with a global prevalence rate of up to 30%, and its prevalence is increasing1. Moreover, MAFLD can progress from simple hepatic steatosis (simple fatty liver, MAFL) to metabolic dysfunction-associated steatohepatitis (MASH), which puts individuals at risk of end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma2. Despite the large number of individuals with MAFLD, poor adherence to lifestyle interventions is observed in clinical practice3, and only limited pharmacological therapy has been approved for MASH4. Therefore, the identification of effective therapeutic targets and strategies for MAFLD is urgently needed.Lysosomal degradation, including the endosome‒lysosome pathway and the autophagy‒lysosome pathway (also known as autophagy), is a pivotal physiological activity essential for maintaining cellular protein homeostasis and has been an appealing platform for drug discovery5,6,7. The membrane of lysosomes harbors a variety of proteins that play critical roles in maintaining lysosomal degradation (preserving the integrity of the lysosomal structure and regulating enzyme activity) and mediating interactions with other organelles or molecules8,9,10,11. The dysregulation of lysosomal membrane proteins can disrupt cellular protein homeostasis, which in turn can cause a spectrum of diseases, including MAFLD12,13,14. Ablation of glycosylated lysosomal membrane protein in mice promotes lipid deposition and causes fibrosis and hepatic cell death in the liver15,16. Moreover, the level of the lysosomal-associated protein transmembrane 5 is negatively correlated with the NAFLD activity score (NAS), and the hepatocyte-specific depletion of lysosomal-associated protein transmembrane 5 exacerbates MASH symptoms in mice17. Our previous studies revealed that transmembrane BAX inhibitor motif-containing protein 1 (TMBIM1) protects against MAFLD by promoting the lysosomal degradation of Toll-like receptor 418. Given the crucial role of lysosomal membrane proteins in lysosomal degradation and their connections in MAFLD, lysosomal membrane proteins could be promising therapeutic targets for MAFLD treatment.Fas apoptotic inhibitory molecule 2 (FAIM2), also known as TMBIM2, belongs to the TMBIM family, which is characterized by a UPF0005 motif that encodes either six or seven transmembrane domains. FAIM2 contains seven transmembrane domains and localizes to lysosomes19; it was initially identified in a study seeking genes involved in the development and maintenance of the nervous system20. Previous studies on FAIM2 have focused mainly on its antiapoptotic effect. Overexpression of FAIM2 protected cortical neurons from FasL-induced apoptosis and decreased caspase activation21, whereas knockdown of FAIM2 expression increased Fas-induced apoptotic cell death in small cell lung cancer cells22. In addition, FAIM2 protects hippocampal cells from death in the acute phase of bacterial meningitis23, reduces stroke volume and alleviates dopaminergic neuron degeneration in Parkinson’s disease24,25. Recently, multiple studies have suggested that single-nucleotide polymorphism mutations at the FAIM2 gene locus are associated with obesity and type 2 diabetes, which are critical risk factors for MAFLD26,27,28,29. However, so far, the role of FAIM2 in MAFLD remains unknown.Here, we identified FAIM2 as an effective suppressor of MAFLD. A marked decrease in FAIM2 protein levels was observed in patients with MAFLD. FAIM2 depletion exacerbated lipid deposition, inflammation and fibrosis in vivo. However, overexpressing FAIM2 in vivo had the opposite effect. Moreover, in hepatocytes, FAIM2 overexpression suppressed the expression of fatty acid synthesis- and inflammation-related genes. Mechanistically, FAIM2 directly interacted with CREB-regulated transcription coactivator 2 (CRTC2), a key regulator of lipid metabolism, and promoted the degradation of CRTC2 via the autophagy pathway. Collectively, our findings suggest that FAIM2 suppresses MAFLD by promoting the autophagic degradation of CRTC2 and further suppressing fatty acid synthesis, suggesting that FAIM2 could be utilized as a therapeutic target for MAFLD.Materials and methodsAnimal treatmentAll animal protocols were approved by the Animal Care and Use Committee of Renmin Hospital of Wuhan University. The animals received humane care according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health.Human liver samplesAll procedures involving the collection of human samples have been approved by the Ethics Committee of Zhongnan Hospital of Wuhan University, and the principles of the Helsinki Declaration have been followed to obtain written informed consent from the participants or their family members. Human liver tissues were obtained from patients clinically undergoing liver biopsy, liver surgery or liver transplantation. Liver tissues excluding alcohol or viral hepatitis were subsequently subjected to hematoxylin and eosin (H&E) staining and scored by one to two expert pathologists.Statistical analysisIn brief, all statistical analyses were performed using SPSS 25.0 (IBM). For data showing a Gaussian distribution, parametric statistical analysis was performed using the two-tailed Student’s t-test for two groups. One-way analysis of variance (ANOVA) was applied to three or more groups, followed by either Bonferroni post-hoc analysis for data meeting homogeneity of variance requirements or Tamhane’s T2(M) post-hoc analysis for heteroscedastic data. For datasets with skewed distributions, nonparametric statistical analysis was performed using the Mann–Whitney U test for two groups and Kruskal–Wallis test for three or more groups. Data are presented as the mean ± s.d., and P