Advances on mechanisms and structural classification of Chinese herbal monomers against hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and mortality. Current therapies face challenges including drug resistance and toxicity. Chinese herbal monomers, characterized by multi-target effects and low toxicity, represent a promising source for anti-HCC drug development. To systematically summarize active Chinese herbal monomers against HCC, classify them by chemical structure, and elaborate their molecular mechanisms. A systematic literature search was initially performed up to December 15, 2025, with an updated search to June 15, 2026. Search terms included combinations of “hepatocellular carcinoma”, “Chinese herbal monomer”, “saponin”, “flavonoid”, “alkaloid”, “terpenoid”, “quinone”, as well as specific compound names and mechanism-related terms such as “apoptosis”, “cell cycle”, “metastasis”, and “drug resistance”. Studies were included if they investigated purified monomers from Chinese herbs with documented anti-HCC activity; reviews, studies on crude extracts without active compound identification, and non-English/Chinese publications were excluded. Data on chemical classification, mechanisms of action, key experimental details (e.g., cell lines, IC₅₀ values, animal models), and signaling pathways were extracted and synthesized narratively by compound class. Chinese herbal monomers exert anti-HCC effects through a multi-dimensional network. They induce various forms of programmed cell death (apoptosis, autophagy, ferroptosis, pyroptosis), inhibit proliferation via cell cycle arrest (G1/S, G2/M), and curb metastasis by suppressing epithelial-mesenchymal transition and invasion-related proteins. They also modulate the tumor microenvironment, reverse multi-drug resistance, and regulate key signaling pathways (phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin, nuclear factor-kappa B, mitogen-activated protein kinases, Wnt/β-catenin). Preliminary structure-activity relationships are observed within compound classes. Chinese herbal monomers demonstrate significant potential as multi-target agents against HCC. However, their clinical translation requires overcoming pharmacokinetic limitations and conducting rigorous clinical validation. Recent advances in drug delivery systems and combination strategies offer promising directions.

Keywords: Hepatocellular carcinoma; Chinese herbal monomers; Flavonoids; Saponins; Apoptosis; Cell cycle arrest; Drug delivery systems; Ferroptosis; Immunomodulation

Core Tip: Hepatocellular carcinoma is a common and deadly liver cancer. This review focuses on active compounds from traditional Chinese herbs, organized by chemical structure. These natural compounds can suppress tumors in multiple ways simultaneously: They induce tumor cell death, block proliferation and metastasis, and modulate the immune microenvironment. By linking chemical structure to biological activity, this review provides a useful guide for developing these compounds into new liver cancer drugs, with an emphasis on recent advances in overcoming translational barriers such as poor bioavailability and lack of clinical evidence.