Monomethyl phthalate promotes hepatocellular carcinoma progression through MMP9 upregulation

Hepatocellular carcinoma (HCC) is recognized as the third leading cause of cancer-related death worldwide, and its epidemiological features are shifting from viral to non-viral etiologies. Phthalates (PAEs) are widely used plastic additives and major indoor environmental pollutants. Monomethyl phthalate (MMP), the primary hepatic metabolite of dimethyl phthalate, possesses endocrine-disrupting and immunosuppressive properties; however, whether a causal association exists between MMP and HCC remains unclear. Two-sample Mendelian randomization (MR) analysis with stringent instrumental variable selection criteria was performed to explore the association between MMP exposure and HCC. In addition, network toxicology, molecular docking, molecular dynamics simulations, together with TCGA database-based differential expression and survival analyses were conducted to identify core targets through which MMP promotes HCC. The specific mechanisms by which MMP facilitates HCC progression were investigated using CCK-8 assays, wound healing assays, and Western blot. MR analysis provided preliminary genetic evidence for a positive association between MMP exposure and elevated HCC risk, with no significant heterogeneity or horizontal pleiotropy detected. MMP promoted the proliferation and migration of HuH-7 cells in a dose-dependent manner. Six core targets were further identified, among which MMP9 was highly expressed in HCC and associated with poor prognosis. Inhibition of MMP9 significantly reversed the MMP-induced pro-carcinogenic effects, indicating that MMP promotes HCC by upregulating MMP9 expression. This study is the first to demonstrate that MMP contributes to HCC pathogenesis through the upregulation of MMP9, providing a novel biomarker and therapeutic target for HCC prevention and environmental risk control.