SWAP70 promotes hepatocellular carcinoma proliferation by enhancing CPT1A-mediated fatty acid β-oxidation under glucose deficiency

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Switch-associated protein 70 (SWAP70) is a unique F-actin binding and bundling protein with multiple domains and broad involvement in various cellular functions. The aim of this study is to investigate the role and mechanism of the SWAP70 in HCC. The expression of SWAP70 in HCC and its prognostic significance were first evaluated using bioinformatics analysis and immunohistochemistry on clinical tissue microarrays. Subsequently, the functional role of SWAP70 in HCC was investigated through both in vitro cell function assays and in vivo mouse experiments. Multi-omics analysis was then employed to explore the underlying mechanism of SWAP70 in HCC. Finally, the therapeutic potential of SWAP70 silencing was assessed in a DEN/CCl₄-induced mouse model of hepatocellular carcinoma. SWAP70 was significantly upregulated in HCC tissues, especially in advanced HCC, and was associated with poor overall survival. SWAP70 promoted HCC cell proliferation in vitro and tumor growth in vivo. Mechanistically, SWAP70 enhanced mitochondrial fatty acid β-oxidation by upregulating carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of this pathway. Silencing CPT1A abrogated SWAP70-mediated proliferative effects. Hepatocyte nuclear factor 4 alpha (HNF4A) acts as a transcriptional repressor of SWAP70. Under glucose deficiency, AMP-activated protein kinase (AMPK) activation suppressed HNF4A expression, thereby promoted expression of SWAP70. Silencing SWAP70 delayed the progression of DEN/CCl₄-induced hepatocellular carcinoma in mice. Collectively, SWAP70 is a key regulator of fatty acid metabolism in hepatocellular carcinoma under glucose deficiency. Targeting SWAP70 represents a promising therapeutic strategy. Diagram of the mechanism of SWAP70 in HCC. SWAP70: Switch-associated protein 70, CCl4: carbon tetrachloride, DEN: Diethylnitrosamine, AAV: adeno-associated virus, NADH: Nicotinamide adenine dinucleotide, FADH: Flavin adenine dinucleotide, ATP: adenosine triphosphate, AMPK: Adenosine monophosphate activated protein kinase, p-AMPK: Phosphorylated AMPK, HNF4A: Hepatocyte nuclear factor 4 alpha. 1. SWAP70 is significantly upregulated in hepatocellular carcinoma tissues and correlates with advanced stage and poor prognosis. 2. Under glucose deficiency, activation of the AMPK HNF4A axis increases SWAP70 expression in hepatocellular carcinoma, which in turn enhances CPT1A-mediated fatty acid β-oxidation to drive tumor proliferation and growth. 3. SWAP70 is a key regulator that promotes fatty acid metabolism in hepatocellular carcinoma under glucose scarcity. 4. Silencing SWAP70 delays the progression of DEN/CCl₄ induced hepatocellular carcinoma in mice. Therefore, targeting SWAP70 may represent a promising therapeutic strategy for hepatocellular carcinoma.