Stachydrine Hydrochloride Suppresses Hepatocellular Carcinoma Progression by Reprogramming Macrophage Polarization Through the LIF/PI3K/Akt Axis
- 1School of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China
- 2Baotou Clinical Medical College, Inner Mongolia Medical University, Baotou 014040, China
- 3School of Basic Medicine, Inner Mongolia Medical University, Hohhot 010010, China
Abstract
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.
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BibTeX
@article{bao2026stachydrine,
title = {{Stachydrine Hydrochloride Suppresses Hepatocellular Carcinoma Progression by Reprogramming Macrophage Polarization Through the LIF/PI3K/Akt Axis}},
author = {Xiaomei Bao and Ye Zhang and Lingjuan Sun and Chunlong He and Dandan Li and Xinran Shi and Yuehong Ma},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219911},
url = {https://www.mdpi.com/1422-0067/27/21/9911},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Stachydrine Hydrochloride Suppresses Hepatocellular Carcinoma Progression by Reprogramming Macrophage Polarization Through the LIF/PI3K/Akt Axis
AU - Xiaomei Bao
AU - Ye Zhang
AU - Lingjuan Sun
AU - Chunlong He
AU - Dandan Li
AU - Xinran Shi
AU - Yuehong Ma
PY - 2026
DA - 2026/11/05
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219911
UR - https://www.mdpi.com/1422-0067/27/21/9911
AB - 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.
SN - 1422-0067
ER -