Objective To investigate the role of caveolin-1 ( CAV1) in the progression of metabolicassociated fatty liver disease (MAFLD) and its potential mechanisms of action. Methods We identified differential CAV1 expressions in normal, obese, and non-alcoholic fatty liver disease individuals based on the human database GSE126848. A CAV1-knockout (KO) MAFLD mouse model was established by feeding with a high-fat diet for 16 weeks. CAV1 protein expression in the liver was determined by albumin and CAV1 co-localization, and CAV1 mRNA and protein levels were detected in primary hepatocytes. Lipid deposition and inflammation were assessed by hematoxylin-eosin, Oil Red O, and Nile Red staining. Mitochondrial damage was observed by transmission electron microscopy. Cellular senescence and iron metabolism changes were evaluated by immunohistochemistry for cyclindependent kinase inhibitor 1A (P21), dihydroethidium staining, and iron staining. We also constructed hepatocyte senescence models and divided them into blank control( Control), palmitic acid ( PA), palmitic acid with CAV1 silencing control group ( PA+Con-siRNA), palmitic acid with CAV1-small interfering RNA( PA+CAV1-siRNA),palmitic acid with CAV1 overexpression control group( PA+Con-GV107), palmitic acid with CAV1 overexpression groups( PA + CAV1-GV146), palmitic acid with CAV1 silencing and deferoxamine group ( PA + CAV1-siRNA +DFO). Lipid deposition, senescence, and Fe²⁺levels were analyzed, and the effects of CAV1 on hepatocyte senescence and mitochondrial function were validated by Western blot, quantitative reverse transcription-polymerase chain reaction, and mitochondrial membrane potential detection (JC-1) assays. Results In vivo experiments showed that the compared with WT+HFD group, KO+HFD exacerbated lipid deposition, inflammation, and liver senescence,as evidenced by enhanced lipid staining, increased levels of senescence markers, including histone H2A variant X phosphorylation, cyclin-dependent kinase inhibitor 2A ( P16), and P21 ( all P<0. 01), decreased levels of the oxidative stress markers glutathione(P<0. 05)and superoxide dismutase(P<0. 01), increased reactive oxygen species (ROS) and malondialdehyde ( P<0. 001), and mitochondrial shrinkage with increased mitochondrial membrane density. CAV1 KO also decreased Fe³⁺(P<0. 01) and increased Fe²⁺ accumulation(P<0. 001), associated with the nuclear receptor coactivator 4-ferritin heavy chain 1 (NCOA4-FTH1) pathway. Compared with KO+HFD+CSD-CON group, supplementation with the CAV1 scaffolding domain significantly improved the reduction of Fe³⁺and the accumulation of Fe²⁺ (both P<0. 01). Compared with the PA+Con-siRNA group, the PA+CAV1-siRNA group showed accelerated lipid accumulation, mitochondrial damage, and cellular senescence, accompanied by elevated mitochondrial reactive oxygen species(mtROS)levels, Fe²⁺ accumulation, increased NCOA4 expression(P<0. 001),and decreased FTH1 expression(P<0. 05), while CAV1 overexpression attenuated these effects(P<0. 05,P<0. 01).Immunofluorescence revealed that CAV1 silencing enhanced NCOA4 and FTH1 co-localization, and this effect was reversed by CAV1 overexpression. Notably, Compared with the PA+CAV1-siRNA group, treatment with deferoxamine (DFO) reduced mtROS levels and ameliorated the senescence induced by CAV1 silencing ( all P<0. 001 ).Collectively, these result indicate that CAV1 modulates liver senescence, potentially via the NCOA4-FTH1 pathway. Conclusions CAV1 can inhibit MAFLD hepatocyte senescence, possibly by regulating iron homeostasis via the NCOA4-FTH1 pathway.