Icaritin eliminates tumor-associated macrophages via STX16-dependent extracellular vesicle delivery of autophagosomes from hepatocellular carcinoma cells
Xia Zheng, Wenshu Qu, Chen Xun, Chao Zhang, Yuan Li, Xinyu Xu, Yang Gao, Yu Gu, Zhihui Yang, Xing Huang, Jun Qian
TL;DR
Icaritin fights liver cancer by reducing harmful macrophages through a chain of metabolic, epigenetic, and autophagy-related processes.
Contribution
Icaritin's novel mechanism targeting ALDOB, STX16, and STAT3 to eliminate M2 TAMs is revealed.
Findings
Icaritin suppresses ALDOB to reduce lactate and H3 lactylation on the STX16 promoter.
STX16 deficiency causes autophagosome accumulation and EV-mediated macrophage death.
Icaritin inhibits tumor growth and M2 TAM infiltration in vivo via the ALDOB/STX16/autophagy/STAT3 axis.
Abstract
To elucidate the mechanism by which icaritin—a novel agent for hepatocellular carcinoma (HCC)—remodels the tumor microenvironment (TME) by inhibiting HCC cell metabolism-mediated M2 polarization of tumor-associated macrophages (TAMs). Integrative approaches spanning in vitro Transwell cocultures, RNA-seq, LC3-based autophagy tracing, STX16 gene edition, and orthotopic xenografts mechanistically dissected the affective and mechanism of icaritin in remodeling TME. Our results indicate that icaritin transcriptionally suppresses ALDOB in HCC cells to reduce lactate production. Consequently, the lactylation of histone H3 at lysine 9 and lysine 18 (H3K9/H3K18la) on the STX16 promoter is diminished, thereby ablating STX16 transcription. STX16 deficiency blocks autophagolysosome biogenesis, leading to the accumulation of autophagosomes in HCC cells. These autophagosomes are subsequently…
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Taxonomy
TopicsMedicinal Plant Pharmacodynamics Research · Autophagy in Disease and Therapy · Immune cells in cancer