APOC3-Mediated Fatty Acid Metabolism Suppresses Lung Adenocarcinoma Progression by Inhibiting GNAI3/cAMP/PKA Pathway

Fatty acid metabolism is a key driver of tumor progression, yet its dysregulation in lung adenocarcinoma (LUAD) remains incompletely characterized. Here, we identify apolipoprotein C3 (APOC3)—previously linked to cardiovascular disease—as a novel suppressor of triglyceride (TG) hydrolysis and fatty acid oxidation, ultimately restraining LUAD growth and metastasis. Proteomic and tissue microarray analyses revealed that APOC3 expression was significantly downregulated in LUAD tissues compared with adjacent normal tissues, and low APOC3 levels correlated with poor prognosis in metastatic patients. Furthermore, plasma levels of APOC3 and TG showed a positive correlation in LUAD patients. Functionally, APOC3 overexpression suppressed TG hydrolysis, fatty acid oxidation, and the proliferation and metastasis of LUAD cells both in vitro and in vivo. Mechanistically, APOC3 attenuated the cAMP/PKA signaling pathway, leading to reduced expression of hormone-sensitive lipase (HSL), a key enzyme in TG hydrolysis, and PGC-1α, a master regulator of fatty acid oxidation. The inhibitory effects of APOC3 on TG hydrolysis and fatty acid oxidation were reversed by cAMP activators or knockdown of HSL or PGC-1α. Additionally, APOC3 was found to interact with GNAI3, a critical inhibitory regulator of the cAMP/PKA pathway. In summary, our study uncovers an APOC3-mediated pathway that constrains TG hydrolysis and fatty acid oxidation, the dysregulation of which contributes to LUAD progression, highlighting APOC3 as a potential therapeutic target in LUAD.