Alcohol activates ATF4/LPLA2-mediated BMP metabolism to enhance HBV-induced hepatocellular carcinogenesis.

BACKGROUND & AIM: Chronic alcohol consumption synergistically enhances hepatocellular carcinoma (HCC) risk in HBV-infected individuals. However, the pivotal molecular mechanisms remain elusive.

METHODS

HBx-transgenic (HBx-Tg) mice and nude mouse xenograft models were used to evaluate the tumor-promoting effects of ethanol. Human liver tissues and serum samples, mouse models, HepG2.215 and Hep3B cell lines were analyzed to assess the expression and oncogenic effects of lysosomal phospholipase A2 (LPLA2). Lipid profiles were assessed using liquid chromatography-mass spectrometry.

RESULTS

Chronic ethanol intake promoted spontaneous tumorigenesis in HBx-Tg mice and accelerated subcutaneous tumor progression in nude mice. Liquid chromatography-mass spectrometry analysis revealed a significant increase in bis(monoacylglycero)phosphate (BMP) species in the tumors of ethanol-fed HBx-Tg mice, attributable to the upregulation of LPLA2. Mechanistic studies showed that activating transcription factor 4 (ATF4) promoted the transcriptional activity of LPLA2 through direct promoter binding. LPLA2 overexpression promoted tumor cell proliferation in vitro and in vivo by activating the MAPK/ERK signaling pathway, whereas LPLA2 silencing effectively abrogated ethanol-promoted hepatocarcinogenesis. Overexpression of BMP synthase CLN5 and BMP supplementation activated the MAPK/ERK signaling pathway, thereby promoting HCC proliferation. Knockdown of CLN5 counteracted the tumor-promoting proliferation of LPLA2. Clinically, the upregulation of LPLA2 is associated with poor prognosis in patients with HCC.

CONCLUSION

Our data demonstrate that alcohol activates ATF4/LPLA2-mediated BMP metabolism, enhancing HBV-induced HCC. LPLA2 may serve as a therapeutic target and prognostic marker in patients with HCC.

IMPACT AND IMPLICATIONS: Chronic alcohol consumption promotes HBV-induced hepatocellular carcinogenesis (HBV-HCC). ATF4/LPLA2-mediated BMP metabolism promotes alcohol-enhanced HBV-HCC via the MAPK/ERK signaling pathway. Targeting LPLA2 or BMP metabolism markedly inhibited HBV-HCC progression. This preclinical study provides a theoretical basis to investigate novel strategies for HCC therapy.