Microhelenin C targets LIF to inhibit hepatocellular carcinoma progression and modulates tumor-associated macrophages
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
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Microhelenin C (MC) is a natural compound that targets LIF in hepatocellular carcinoma (HCC).
MC promotes LIF degradation and inhibits HCC cell growth, migration, and invasion.
MC reduces HCC tumor growth in mice without causing obvious systemic toxicity.
MC also promotes an M1-like phenotype in tumor-associated macrophages.
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ABSTRACT
Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality worldwide, underscoring the urgent need for effective therapeutic strategies. Leukemia inhibitory factor (LIF) has emerged as an important regulator of HCC progression and represents a promising therapeutic target. However, effective pharmacological approaches targeting LIF remain limited. In this study, we investigated Microhelenin C (MC), a natural sesquiterpene lactone derived from Centipeda minima, and demonstrated its potent anti-HCC activity. Specifically, MC inhibited cell proliferation, migration, and invasion, while inducing apoptosis in HCC cells. Mechanistically, MC directly engaged LIF and inhibited downstream STAT3 signaling. Moreover, LIF overexpression attenuated the antitumor effects of MC, further supporting a functional role for LIF in mediating the anti-HCC activity of MC. Beyond its tumor-intrinsic effects, MC also modulated the tumor microenvironment (TME) by promoting macrophage polarization toward an M1-like phenotype while suppressing M2-associated characteristics. These immunomodulatory effects were consistently observed in both co-culture systems and orthotopic HCC models. Collectively, our findings identify LIF as a therapeutically relevant target in HCC and demonstrate that MC exerts both direct anti-tumor and immunomodulatory effects. This study provides mechanistic insight into the anti-HCC activity of MC and supports the development of LIF-targeted therapeutic strategies in HCC. -
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REFERENCES
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Gong R., Shen L., Chen J., et al. (2026). Microhelenin C targets LIF to inhibit hepatocellular carcinoma progression and modulates tumor-associated macrophages. The Innovation Drug Discovery 1:100040. https://doi.org/10.59717/j.xinn-drugdisc.2026.100040
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Gong R., Shen L., Chen J., et al. (2026). Microhelenin C targets LIF to inhibit hepatocellular carcinoma progression and modulates tumor-associated macrophages. The Innovation Drug Discovery 1:100040. https://doi.org/10.59717/j.xinn-drugdisc.2026.100040
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Figure 1.
MC suppresses malignant phenotypes of HCC cells in vitro
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Figure 2.
MC inhibits migration, invasion, and apoptosis-related phenotypes of HCC cells in vitro
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Figure 3.
MC suppresses tumor growth in a Huh7 xenograft model
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Figure 4.
LIF is identified as a potential therapeutic target in HCC
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Figure 5.
MC targets LIF to mediate its anti-HCC effects
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Figure 6.
MC promotes macrophage polarization toward an M1-like phenotype
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Figure 7.
MC suppresses orthotopic HCC tumor growth in vivo
