Myocardin-related transcription factors A and B (MRTFs) are coactivators of Serum Response Factor (SRF), which controls fundamental biological processes such as cell growth, migration, and differentiation. MRTF and SRF transcriptional activity play an important role in hepatocellular carcinoma (HCC) growth, which represents the second leading cause of cancer-related mortality in humans worldwide. We, therefore, searched for druggable targets in HCC that regulate MRTF/SRF transcriptional activity and can be exploited therapeutically for HCC therapy. We identified the G protein-coupled lysophosphatidic acid receptor 1 (LPAR1) as a novel interaction partner of MRTF-A and Filamin A (FLNA) using fluorescence resonance energy transfer-(FRET) and proximity ligation assay (PLA) in vitro in HCC cells and in vivo in organoids. We found that LPAR1 promotes FLNA phosphorylation at S2152 which enhances the complex formation of FLNA and MRTF-A, actin polymerization, and MRTF transcriptional activity. Pharmacological blockade or depletion of LPAR1 prevents FLNA phosphorylation and complex formation with MRTF-A, resulting in reduced MRTF/SRF target gene expression and oncogene-induced senescence. Thus, inhibition of the LPAR1–FLNA–MRTF-A interaction represents a promising strategy for HCC therapy.

心肌素相关转录因子 A 和 B (MRTF) 是血清反应因子 (SRF) 的共激活因子，它控制细胞生长、迁移和分化等基本生物过程。MRTF 和 SRF 转录活性在肝细胞癌 (HCC) 的生长中起着重要作用，它是全世界人类癌症相关死亡率的第二大主要原因。因此，我们在 HCC 中寻找可调节 MRTF/SRF 转录活性并可用于 HCC 治疗的药物靶标。我们在 HCC 细胞中使用荧光共振能量转移 (FRET) 和邻近连接试验 (PLA) 在体外将 G 蛋白偶联的溶血磷脂酸受体 1 (LPAR1) 鉴定为 MRTF-A 和细丝蛋白 A (FLNA) 的新型相互作用伙伴和体内的类器官。我们发现 LPAR1 促进 S2152 处的 FLNA 磷酸化，从而增强 FLNA 和 MRTF-A 的复合物形成、肌动蛋白聚合和 MRTF 转录活性。LPAR1 的药理学阻断或消耗可防止 FLNA 磷酸化和与 MRTF-A 形成复合物，从而导致 MRTF/SRF 靶基因表达减少和致癌基因诱导的衰老。因此，抑制 LPAR1–FLNA–MRTF-A 相互作用代表了一种有前途的 HCC 治疗策略。