SLC25A20 promotes tumor growth by reprogramming energy metabolism in lung adenocarcinoma.

Abstract

Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. The molecular alterations in tumors that promote metabolic diversity and distinct targetable dependencies remain poorly defined. The mitochondrial transporter SLC25A20, also known as carnitine-acylcarnitine translocase (CACT), is crucial for fatty acid β-oxidation (FAO) by importing acylcarnitines into the mitochondrial matrix. Here, we demonstrate that SLC25A20 is significantly upregulated in lung adenocarcinoma (LUAD) tissues and cells, and its expression correlates with poor patient survival. Gain- and loss-of-function experiments reveal that SLC25A20 promotes tumor cell proliferation, survival, migration, and invasion by enhancing FAO-associated mitochondrial bioenergetics and suppressing apoptosis. Mechanistically, SLC25A20-mediated FAO maintains mitochondrial function and supports oxidative phosphorylation (OXPHOS), thereby sustaining tumor bioenergetics and redox homeostasis. Pharmacological inhibition or genetic silencing of SLC25A20 impairs tumor growth in vivo. These findings establish SLC25A20 as a key metabolic driver in LUAD and suggest it may be a therapeutic target.