Abstract: Objective To investigate the role of elongation of very long-chain fatty acids protein 1（ELOVL1） gene in mediating cisplatin sensitivity in ovarian cancer via epigenetic regulation, and to provide potential targets and theoretical basis for reversing cisplatin resistance. Methods Cisplatin sensitivity was evaluated in 11 human ovarian cancer cell lines by determining the half-maximal inhibitory concentration(IC₅₀). Based on IC₅₀ values, the cell lines were classified into sensitive, intermediate, and resistant groups. Total RNA was extracted from eight cell lines, and differentially expressed genes were screened using an mRNA microarray. ELOVL1 expression was validated by reverse transcription quantitative polymerase chain reaction（RT-qPCR）. Methylation levels of CpG sites within the ELOVL1 promoter region were assessed using the Infinium^® HumanMethylation450 BeadChip array. Cells were treated with 5-aza-2'-deoxycytidine（5-aza-dC）, and changes in ELOVL1 expression were measured. The effect of ELOVL1 on cisplatin sensitivity was examined via ELOVL1 overexpression and small interfering RNA（siRNA） knockdown experiments, in combination with a 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） assay and detection of cysteinyl aspartate-specific proteinase 3（Caspase-3） cleavage. Results The IC₅₀ values of cisplatin across the 11 ovarian cancer cell lines in ascending order were PA-1, TOV-21G, TOV-112D, Caov-3, A2780, MDAH-2774, A2780 cis, ES-2, OVCAR-3, OV-90, and SK-OV-3. ELOVL1 mRNA expression was significantly lower in resistant cell lines than in sensitive cell lines（P< 0.05）. Methylation array analysis showed that the methylation at the +251 CpG site in the ELOVL1 promoter in resistant cell lines was significantly higher than that in sensitive cell lines（P< 0.05）. Treatment with 5-aza-dC restored ELOVL1 expression in resistant cell lines（P< 0.05）. ELOVL1 overexpression reduced the cisplatin IC₅₀ by 13% in SK-OV-3 cells and by 49% in TOV-112D cells（both P< 0.05）; whereas ELOVL1 knockdown increased the cisplatin IC₅₀ by 22% and 66%, respectively（both P< 0.05）. Moreover, ELOVL1 overexpression enhanced cisplatin-induced Caspase-3 cleavage, while ELOVL1 knockdown attenuated this effect（both P< 0.05）. Conclusion ELOVL1 may regulate cisplatin sensitivity in ovarian cancer through epigenetic silencing mediated by promoter hypermethylation, and its molecular mechanism may involve the regulation of the Caspase-3-dependent apoptotic pathway by lipid metabolism reprogramming. ELOVL1 is expected to serve as a potential epigenetic therapeutic target for reversing cisplatin resistance.