Iranian journal of pharmaceutical research : IJPR · 2026
Baicalein Attenuates Early Molecular and Proliferative Changes in MASH-Driven Hepatocarcinogenesis by Inhibiting the NLRP3 Inflammasome and Pyroptosis Pathway.
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Xu Jing, Bostani Amirabas, Qu Hongwei
Аннотация
BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a major risk factor for hepatocellular carcinoma (HCC). The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and pyroptosis are key drivers of inflammation and tumorigenesis. Baicalein (BAI), a flavonoid derived from Scutellaria baicalensis, has anti-inflammatory and antitumor properties.
OBJECTIVES: This study aimed to evaluate the effects of BAI on early molecular and proliferative changes in a MASH-driven hepatocarcinogenesis model, using validated surrogate markers of preneoplastic progression (Ki-67 and glutathione S-transferase pi 1 [GSTP1]) rather than direct histopathological tumor quantification.
METHODS: An M-HCC rat model was established using a hepatopathogenic diet, carbon tetrachloride, and diethylnitrosamine. Rats received BAI (50 mg/kg/day) orally for 16 weeks. Biochemical, oxidative stress, and fibrosis parameters were measured, and the expression of NLRP3 inflammasome components, inflammatory cytokines, and proliferation markers was assessed. The findings were validated in lipotoxic HepG2 cells treated with BAI, with or without the NLRP3 inhibitor MCC950.
RESULTS: BAI significantly reduced serum liver enzyme levels, oxidative stress, and fibrosis markers in M-HCC rats. BAI treatment was associated with reduced NLRP3 inflammasome activation and pyroptosis marker levels, as evidenced by decreased levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, the N-terminal fragment of gasdermin D (GSDMD-N), IL-1β, and IL-18, together with reduced steatosis and proliferation markers. In lipotoxic HepG2 cells, BAI dose-dependently suppressed NLRP3 activation and pyroptosis; cotreatment with MCC950 did not further enhance these effects.
CONCLUSIONS: BAI treatment was associated with suppression of components of the NLRP3 inflammasome and pyroptosis pathways, as well as reductions in inflammatory, fibrotic, and proliferative markers. These findings support further investigation of BAI as a candidate for modulating early hepatocarcinogenic events. However, direct anti-HCC efficacy remains to be established in future studies incorporating histological tumor endpoints.
OBJECTIVES: This study aimed to evaluate the effects of BAI on early molecular and proliferative changes in a MASH-driven hepatocarcinogenesis model, using validated surrogate markers of preneoplastic progression (Ki-67 and glutathione S-transferase pi 1 [GSTP1]) rather than direct histopathological tumor quantification.
METHODS: An M-HCC rat model was established using a hepatopathogenic diet, carbon tetrachloride, and diethylnitrosamine. Rats received BAI (50 mg/kg/day) orally for 16 weeks. Biochemical, oxidative stress, and fibrosis parameters were measured, and the expression of NLRP3 inflammasome components, inflammatory cytokines, and proliferation markers was assessed. The findings were validated in lipotoxic HepG2 cells treated with BAI, with or without the NLRP3 inhibitor MCC950.
RESULTS: BAI significantly reduced serum liver enzyme levels, oxidative stress, and fibrosis markers in M-HCC rats. BAI treatment was associated with reduced NLRP3 inflammasome activation and pyroptosis marker levels, as evidenced by decreased levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, the N-terminal fragment of gasdermin D (GSDMD-N), IL-1β, and IL-18, together with reduced steatosis and proliferation markers. In lipotoxic HepG2 cells, BAI dose-dependently suppressed NLRP3 activation and pyroptosis; cotreatment with MCC950 did not further enhance these effects.
CONCLUSIONS: BAI treatment was associated with suppression of components of the NLRP3 inflammasome and pyroptosis pathways, as well as reductions in inflammatory, fibrotic, and proliferative markers. These findings support further investigation of BAI as a candidate for modulating early hepatocarcinogenic events. However, direct anti-HCC efficacy remains to be established in future studies incorporating histological tumor endpoints.