Abstract PR010: Lipid-droplet associated hydrolase (LDAH) dysregulates lipid metabolism and polarization of TAMs in ovarian cancer

Abstract Metabolic reprograming modulates the polarization of tumor-associated macrophages (TAMs) to profoundly influence tumor progression in ovarian cancer. Lipid droplet-associated hydrolase (LDAH) is a lipid hydrolase abundantly expressed in adipose and ovarian tissues and macrophages. Low levels of LDAH in ovarian cancer are associated with increased tumor growth by increasing Fatty acid oxidation (FAO) in ovarian cancer. However, how LDAH in macrophages can affect ovarian cancer progression is largely unknown. In this study, we used LDAH KI and LDAH KO mouse model to investigate the role of LDAH in ovarian cancer TAMs. Firstly, our results showed that LDAH KI mice exhibited better survival outcomes as compared to LDAH KO mice. Further, we isolated peritoneal macrophages from LDAH KI and KO mice and our results showed that LDH KI mice predominantly showed pro-inflammatory M1 macrophage phenotype while LDAH KO mice showed anti-inflammatory M2 macrophage phenotype. Since lipid-loaded macrophages show more M2 macrophage phenotype, our results also showed that LDAH KO macrophages showed more accumulation of lipid droplets as compared to LDAH KI mice. Conventionally, M2-like macrophages rely on FAO to meet bioenergetic demands, therefore, we determined the effect of LDAH on FAO in macrophages. Our invitro results further confirmed that LDAH KD macrophages showed increased level of PPAR-γ and FASN—hallmarks of altered lipid metabolism associated with M2 polarization. Inhibition of FAO in LDAH KD macrophages further decreased the M2 phenotype and lipid droplet accumulation in TAMs, thus suggesting that LDAH regulates macrophage phenotype through modulation of lipid metabolism and FAO and highlight its potential as a therapeutic target for reprogramming TAMs in ovarian cancer. Citation Format: Bhawna Deswal, Dong-Joo Cheon. Lipid-droplet associated hydrolase (LDAH) dysregulates lipid metabolism and polarization of TAMs in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR010.