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Adv."],"published-print":{"date-parts":[[2026,5,15]]},"abstract":"<jats:p>Prevention remains a key strategy to address the growing burden of metabolic dysfunction\u2013associated steatotic liver disease (MASLD), highlighting the importance of exploring modifiable risk factors. Accumulating evidence suggests a close link between physical frailty and MASLD. However, how frailty interacts with metabolic syndrome to affect MASLD and the causality and direction of the association remain largely unknown. Leveraging data from 405,224 UK Biobank participants with a 13.65-year follow-up, we found that physical frailty was associated with an increased risk of clinically diagnosed MASLD and exacerbated the adverse effect of metabolic syndrome on MASLD incidence, implying that frail people may be more vulnerable to this disease because of metabolic syndrome. Mendelian randomization provided evidence for a potential causal effect of physical frailty on MASLD but not the reverse direction. 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