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A Novel Function of the Branched-Chain Fatty Acid iso15:0 in Suppressing HCC Malignant Progression through GPCR/PI3K/AKT Pathway Inhibition

ABSTRACT: Despite advances in hepatocellular carcinoma (HCC) treatment, the discovery of novel bioactive molecules with well-defined mechanisms remains a critical need. This study identifies the branched-chain fatty acid iso15:0 as a potent suppressor of HCC progression and delineates its underlying molecular pathway. We demonstrated that iso15:0 significantly inhibits the proliferation and migration of HCC cells in vitro and suppresses tumor growth and metastasis in vivo. Transcriptomic profiling of treated cells revealed widespread alterations in gene expression, with Gene Set Enrichment Analysis (GSEA) pinpointing a significant suppression of the GPCR signaling pathway. Subsequent mechanistic investigations established that iso15:0 executes its function by specifically targeting the Gβγ subunits of heterotrimeric G proteins, thereby disrupting the downstream activation of the PI3K/AKT signaling cascade. This inhibition leads to cell cycle arrest and suppression of epithelial-mesenchymal transition (EMT). Our findings unveil a previously unrecognized tumor-suppressive function of iso15:0 and define a novel mechanism by which it inhibits HCC progression through targeted interference with the Gβγ–PI3K/AKT signaling axis. This work not only provides a mechanistic basis for the anti-tumor activity of iso15:0 but also highlights its potential as a promising lead compound for the development of new molecularly-targeted therapies against HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312291 | GEO | 2025/12/07

REPOSITORIES: GEO

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Project description:Introduction: Primary liver cancer remains the third leading cause of global cancer-related mortality, with hepatocellular carcinoma (HCC) constituting the predominant histological subtype. The development of malignant ascites in advanced HCC patients signifies metastatic progression and portends poor clinical outcomes, presenting a formidable therapeutic challenge.Objectives: This study aimed to engineer a natural small-molecule hydrogel for anti-tumor treatment, in order to reduce the production of ascites and achieve the dual therapeutic effect. Methods: The EP-GA hydrogel was synthesized by a one-pot method, and its morphology and mechanical properties were characterized by SEM and rheology. UHPLC-Q-Orbitrap HRMS analysis was carried out to identify the active components of EP. The assembly mechanism was analyzed by 1H-NMR and molecular dynamics. Small animal imaging techniques were utilized to evaluate the retention of EP-GA in vivo. The H22 ascites tumor model was established, and antitumor mechanism was verified by transcriptomics, metabolomics and flow cytometry.Results: The EP-GA hydrogel formed uniform nanoparticles with an average diameter of approximately 200 nm. Rheological characterization confirmed its excellent injectability. Using marker components euphol (EPH) and glycyrrhizic acid (GA) to analyze the self-assembly process, hydrogen bond interactions occurred between euphol's hydroxyl group and GA's hydrophilic domain. In H22 subcutaneous HCC xenograft models, EP-GA demonstrated significant tumor growth suppression, with a tumor growth inhibition rate (IRG) of 68.63% at the dosage of 18.75 mg/kg. Combined transcriptomic and metabolomic analysis reveals that it inhibits tumor progression by suppressing choline kinase alpha, regulating the PI3K/AKT/mTOR pathway, and inducing ROS generation and mitochondrial membrane potential decline.Conclusion: This excipient-free nanohydrogel platform effectively circumvents carrier-related toxicity while demonstrating powerful therapeutic efficacy against HCC, and this platform is a promising new strategy for HCC prevention and treatment.

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A Novel Function of the Branched-Chain Fatty Acid iso15:0 in Suppressing HCC Malignant Progression through GPCR/PI3K/AKT Pathway Inhibition

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