Hepatic stellate cell-specific METTL3 deficiency promotes hepatocellular carcinoma progression via BMP10-SMAD1/5/8 signaling

Hepatic stellate cells (HSCs) and their derived cancer-associated fibroblasts (CAFs) are integral to the development, progression, and prognosis of hepatocellular carcinoma (HCC). However, the mechanisms underlying the transformation of HSCs into CAFs and their subsequent roles in HCC remain incompletely understood. The expression of METTL3 was analyzed in fibroblasts infiltrating into human HCC specimens compared to adjacent non-tumor tissues. The effects of HSC-specific METTL3 deficiency on HCC were analyzed by orthotopically transplanting hepatoma cells into the mouse fibrotic liver and directly or indirectly co-culturing hepatoma cells with HSCs. We found that the expression of METTL3, the methyltransferase responsible for RNA N6-methyladenosine (m6A) modification, was downregulated in fibroblasts infiltrating into HCC compared to that of adjacent non-tumor tissues. Orthotopical transplantation of HCC cells in fibrotic liver showed that HSC-specific METTL3 deficiency significantly increased tumor burden. Meanwhile, conditioned medium treatment and mixed co-culture confirmed that METTL3 deletion in HSCs promoted HCC proliferation and migration in vitro, demonstrating that METTL3 deficiency in HSCs accelerated HCC progression in fibrotic liver. Mechanistically, METTL3 deficiency reduced m6A modification and expression of BMP10, a known tumor suppressor. Similar to the effects of METTL3 deficiency, BMP10 knockdown also promoted hepatoma cell growth, while recombinant BMP10 (rBMP10) inhibited it. Overexpression of BMP10 or addition of rBMP10 mitigated the tumor-promoting effects of METTL3-deficient HSCs. BMP10's effects were mediated through SMAD1/5/8 phosphorylation. Our study reveals a novel crosstalk between HSCs and hepatoma cells via the METTL3/m6A-BMP10-SMAD1/5/8 axis, suggesting a potential therapeutic target for HCC.