Integration of scRNA-seq and bulk RNA-seq to reveal the association and potential molecular mechanisms of metabolic reprogramming regulated by lactylation and chemotherapy resistance in ovarian cancer

Objective: Ovarian cancer (OC) ranks among the foremost causes of mortality in gynecological malignancies, with chemoresistance being the primary factor contributing to unfavorable prognosis. This work seeks to clarify the mechanisms of resistance-related lactylation in OC, intending to offer novel theoretical foundations and therapy strategies for addressing chemoresistance. Methods: Through the combined analysis of bulk RNA-seq and single-cell RNA-seq data, we initially found lactylation genes linked to chemoresistance. Subsequently, we employed differential expression analysis, survival analysis, enrichment analysis, and other methodologies to further investigate the roles and molecular mechanisms of these genes in tumor resistance. Ultimately, we investigated the differential expression of these genes in resistant and non-resistant tissues and cells via experimentation. Results: We found two candidate genes associated with lactylation chemoresistance, ALDH1A1 and S100A4. Analysis of single-cell data indicated that tumor cells represent the primary cell subpopulation relevant to resistance studies. Subpopulation analysis indicated that several tumor cell subtypes were markedly linked to resistance, with elevated expression levels of ALDH1A1 and S100A4 in the resistant subpopulation, notably correlating with various immunological and metabolic pathways. Analysis of metabolic pathways indicated that oxidative phosphorylation and glycolysis activity was elevated in the resistant subpopulation, and lactic acid buildup was associated with chemoresistance. The investigation of the marker gene protein-protein interaction network in the resistant subgroup elucidated the intricate interactions among these genes. The expression levels of ALDH1A1 and S100A4 in the OC tissues of the platinum-resistant cohort were markedly elevated compared to the sensitive cohort, with a considerable rise in S100A4 expression observed in resistant OC cells, demonstrating co-localization with lactylation. Conclusion: This work elucidates the significant function of lactylation in OC chemoresistance and identifies ALDH1A1 and S100A4 as possible genes associated with drug resistance. These findings enhance our comprehension of the mechanisms behind chemoresistance in OC and offer critical insights for the formulation of novel therapeutic options.