Background <p>Ovarian cancer (OC) remains a highly lethal gynaecologic malignancy. Endothelial cell-specific molecule 1 (ESM1) and protein lysine L-lactylation modification (Pan-kla) are key players in tumour microenvironment regulation, which involves metabolic reprogramming, angiogenesis, and immune modulation. However, their coexpression patterns, clinical relevance, and synergistic prognostic impact in OC patients have not been fully elucidated.</p> Methods <p>In this study, immunohistochemistry (IHC) was used to analyse ESM1 and Pan-kla expression in 131 ovarian cancer tissue samples from patients diagnosed between 2014 and 2024. Clinical parameters (e.g., FIGO stage, CA125 level, and ascites) and survival data were collected. Statistical analyses, including Kaplan–Meier survival and risk stratification, were performed using R software.</p> Results <p>ESM1 and Pan-kla were significantly overexpressed in OC tissues, with a strong positive correlation (<i>P</i> &lt; 0.0001). High expression of both biomarkers was associated with adverse clinical features: advanced FIGO stage, elevated CA125 levels, and malignant ascites. Survival analysis revealed that high ESM1 expression increased the risk of death, whereas high Pan-kla expression increased the risk. Patients exhibiting combined ESM1/Pan-kla expression were stratified into four prognostic subgroups, with the dual-high group exhibiting the worst survival (<i>P</i> &lt; 0.001).</p> Conclusion <p>ESM1 and Pan-kla synergistically promote OC progression through metabolic–epigenetic cross-regulatory mechanisms. Their combined assessment provides robust prognostic stratification and reveals potential targets for overcoming therapeutic resistance in ovarian cancer.</p> Graphical Abstract <p></p>