To estimate the individual and combined influences of phthalates and biological aging on insulin resistance (IR), prediabetes, and diabetes in population with metabolic dysfunction-associated steatotic liver disease (MASLD).

Data on 3,045 US adults with MASLD were collected to outline the individual and mixed effects of urinary phthalate metabolites on prevalent IR, prediabetes, and diabetes by survey-weighted logistic regression and weighted quantile sum (WQS) regression, as well as the interaction effects between phthalates and biological aging.

We discovered positive relationships – odds ratio (OR) and 95 % confidence interval [CI] – of mono-2-ethyl-5-carboxypentyl phthalate 1.147 [1.041;1.264], mono-(2-ethyl-5-hydroxyhexyl) phthalate 1.175 [1.073;1.288], and mono-(2-ethyl-5-oxohexyl) phthalate 1.140 [1.040;1.250] with IR, and of mono-isobutyl phthalate with prediabetes 1.216 [1.064;1.390] (all FDR-adjusted P < 0.05). WQS analyses indicated significantly mixed effects of phthalate metabolites on the elevated risks of IR 1.166 [1.034;1.315], prediabetes 1.194 [1.006;1.416], and diabetes 1.214 [1.026;1.437]. Biological age (BA) and phenotypic age (PA) were positively associated with IR, prediabetes, and diabetes and further significantly interacted with phthalates on the outcomes; typically, compared to participants with low levels of phthalates mixture and PA, those with high levels of phthalates mixture and PA had the highest risks of IR 2.468 [1.474;4.133] (P_interaction = 0.031), prediabetes 1.975 [1.189;3.278] (P_interaction = 0.009), and diabetes 6.065 [3.210;11.460] (P_interaction = 0.013).

Phthalates exposure of MASLD adults was related to increased risks of IR, prediabetes, and diabetes, which were interactively aggravated by biological aging. Controlling phthalates exposure and biological aging probably hold significant relevance for the prevention of diabetes in the MASLD population.