<p>Ferroptosis is closely associated with the progression of metabolic-associated fatty liver disease (MAFLD). Paris saponin VII (PP7), a steroidal saponin extracted from the rhizomes of <i>Paris polyphylla</i>, has been shown to regulate ferroptosis. However, whether PP7 affects MAFLD progression by modulating ferroptosis remains unclear. In vivo and in vitro MAFLD models were established using high-fat diet (HFD)-induced rats and oleic acid (OA)-induced HepG2 cells. Hematoxylin‒eosin (HE) staining was used to detect pathological changes in liver tissues, and Oil Red O staining was used to assess lipid accumulation levels in liver tissues. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were used to evaluate insulin resistance. Assay kits were used to measure the levels of TC, TG, FFA and ferroptosis-related indicators. RT‒qPCR, Western blot, immunohistochemistry, and immunofluorescence analyses were used to detect the expression of related genes and proteins, while coimmunoprecipitation was performed to examine protein interactions. PP7 treatment improved hepatic steatosis, reduced lipid accumulation, and alleviated insulin resistance in MAFLD rats. Treatment of HepG2 cells with PP7 mitigated the OA-induced decrease in cell viability, increased glucose uptake capacity, and decreased TC, TG, and FFA levels. PP7 also reduced the levels of Fe²⁺, MDA, ROS, TFR, and ACSL4 but increased the levels of SOD, GSH, SLC7A11, and GPX4, thereby inhibiting ferroptosis and alleviating cellular damage. Mechanistically, USP7 was underexpressed in MAFLD, and USP7 expression was positively regulated by PP7. USP7 interacted with SLC7A11 and stabilized its expression through deubiquitination. The protective effects of PP7 were significantly attenuated by the USP7 inhibitor P5091 and the SLC7A11 inhibitor HG106. PP7 enhances the deubiquitination of SLC7A11 by upregulating USP7 expression and promoting SLC7A11 expression, thereby inhibiting ferroptosis and alleviating MAFLD progression.</p>