What question did this study set out to answer?

The research aims to explore how LDHA and ACAA2 lactylation influence fatty acid metabolism and ccRCC progression.

April 23, 2026Open Access

LDHA-driven ACAA2 lactylation at K270 reprograms fatty acid metabolism to promote clear cell renal cell carcinoma progression

YCYong ChenFirst Affiliated Hospital of Henan University of Science and Technology YWYaqian WangLuoyang Orthopedic-Traumatological Hospital of Henan Province XNXiaoyuan NingPeking University

Key Points

The research aims to explore how LDHA and ACAA2 lactylation influence fatty acid metabolism and ccRCC progression.
Conducted lactylome profiling to identify modified sites
Performed functional assays for LDHA overexpression and knockdown
Used structural and biochemical analyses to assess ACAA2 activity
Identified ACAA2 K270 lactylation as a key regulator of ccRCC progression
Demonstrated that LDHA upregulation correlates with shorter patient survival
Showed that increased free fatty acids promote cancer cell proliferation, migration, and invasion

Abstract

This study elucidates a novel lactate dehydrogenase A (LDHA)-acetyl CoA acyltransferase 2 (ACAA2)-lactylation axis driving clear cell renal cell carcinoma (ccRCC) progression through metabolic reprogramming. LDHA upregulation in ccRCC tissues is clinically linked to shorter overall patient survival. Functional assays demonstrated that LDHA overexpression enhances ccRCC proliferation, migration, and invasion, while knockdown attenuated these effects. Lactylome profiling identified 59 modified sites and revealed ACAA2 K270 lactylation (ACAA2-K270la) as a key regulator. Structural and biochemical analyses revealed K270 lactylation increases ACAA2 activity, promoting free fatty acids (FFAs) elevation. Exogenous FFAs recapitulated pro-tumorigenic effects in a dose-dependent manner. Mechanistically, LDHA-mediated ACAA2-K270la upregulated cyclins and cyclin-dependent kinases (CDKs), linking metabolic rewiring to cell cycle progression. These findings establish lactylation as a critical metabolic checkpoint in ccRCC, and reveal new therapeutic targets for metabolic intervention.

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