Stachydrine Hydrochloride Suppresses Hepatocellular Carcinoma Progression by Reprogramming Macrophage Polarization Through the LIF/PI3K/Akt Axis

Hepatocellular carcinoma (HCC) carries a poor prognosis, largely owing to an immunosuppressive tumor immune microenvironment (TIME) shaped by M2-polarized tumor-associated macrophages (TAMs). Stachydrine hydrochloride (SH), an alkaloid derived from Panzeria alashanica Kupr., exerts anti-inflammatory and anti-tumor effects; however, its immunomodulatory action in HCC remains unclear. Here, we investigated whether SH restrains HCC progression by regulating TAM polarization through the LIF/PI3K/AKT pathway, using RAW264.7, THP-1, HepG2, and Huh-7 cells; a subcutaneous tumor model; and bioinformatic analysis of clinical samples. SH modulated macrophage phenotypes dose-dependently without obvious cytotoxicity, promoting M1 polarization while suppressing M2 polarization and autophagy in M2 macrophages, and enhanced macrophage phagocytosis of HCC cells. Conditioned medium from SH-treated M2 macrophages inhibited HCC cell proliferation, migration, and epithelial–mesenchymal transition. Mechanistically, SH suppressed LIF/PI3K/AKT activation in M2 macrophages, and LIF overexpression showed a trending capacity to partially counteract SH-mediated M2-suppressive effects. Bioinformatics linked high M2-TAM infiltration with poor HCC prognosis. In vivo, SH retarded tumor growth, decreased intratumoral M2-TAM infiltration, and reduced Ki-67 levels. Collectively, SH remodels the TIME to restrain HCC progression, and these effects are associated with inhibition of M2-TAM polarization and attenuation of LIF/PI3K/Akt signaling, revealing a novel immunotherapeutic mechanism and supporting SH as a promising natural agent for HCC immunotherapy.