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Liver Disease Diagnosis and Treatment / Inflammasome and Immune Disorders / Liver Diseases and Immunity · Journal article
Frontiers in Immunology · September 9, 2026
Encouraging direction, but not yet definitive.
Smilax glabra flavonoids suppress HFD-induced NASH in mice by inhibiting PKM2-dependent glycolysis and AIM2 inflammasome activation in macrophages, with hepatoprotective effects demonstrated through mechanistic validation in co-culture models. This preclinical study identifies a plausible therapeutic target but lacks clinical efficacy or safety data.
In vivo controlled animal study with in vitro mechanistic validation and co-culture models. C57BL/6J mice; AML-12 mouse hepatocyte cell line; RAW264.7 mouse macrophage cell line. Intervention: Smilax glabra flavonoids (SGF) at 30 or 90 mg/kg/day; lentiviral PKM2 overexpression in macrophages. Compared with: Empagliflozin (EMPA); vehicle control; siRNA-mediated PKM2 knockdown; macrophage co-culture with and without PKM2 overexpression.
SGF (30 or 90 mg/kg/day) markedly attenuated HFD-induced obesity, dyslipidemia, hepatic steatosis, fibrosis and hepatocellular damage SGF downregulated HK2, p-PKM2, and LDHA and reduced pyruvate and lactate production in glycolytic pathway SGF decreased levels of AIM2, ASC, caspase-1, and IL-1β in inflammasome signaling
No human data, clinical safety data, or bioavailability of SGF reported
These findings suggest a potential mechanism by which plant-derived flavonoids may benefit NASH patients, but clinical trials are required before any therapeutic recommendation can be made. The macrophage-hepatocyte crosstalk through PKM2 offers a rational target for drug development.
Mechanistic study in animal models and cell culture demonstrating SGF efficacy against NASH through multiple pathways; results are convincing within the experimental system but require clinical translation.
As stated by the source record.
Quoted from the source exactly as published.
These findings suggest a potential mechanism by which plant-derived flavonoids may benefit NASH patients, but clinical trials are required before any therapeutic recommendation can be made. The macrophage-hepatocyte crosstalk through PKM2 offers a rational target for drug development.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Background Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver disease characterized by hepatic steatosis, persistent inflammation and progressive liver damage. Smilax glabra flavonoids (SGF), the major bioactive constituents of Smilax glabra Roxb., exhibit potent antioxidant and anti-inflammatory activities. Nevertheless, their therapeutic role and molecular basis in NASH remain elusive. Methods This study aimed to investigate the protective effects of SGF against high-fat diet (HFD)-induced NASH in mice, with emphasis on PKM2-mediated glycolysis and AIM2 inflammasome activation. C57BL/6J mice were fed an HFD for 20 weeks to establish a NASH model and concurrently treated with SGF (30 or 90 mg/kg/day) or empagliflozin (EMPA). Comprehensive assessments, including biochemical detection, histological staining and molecular biological verification, were performed. In vitro, FFA-challenged AML-12 hepatocytes and LPS-stimulated RAW264.7 macrophages were adopted. siRNA-mediated knockdown, lentiviral overexpression, and cell co-culture models were further applied to validate the underlying mechanisms. Results SGF markedly attenuated HFD-induced obesity, dyslipidemia, hepatic steatosis, fibrosis and hepatocellular damage, mitigated hepatic oxidative stress and restored mitochondrial structure integrity. Mechanistically, SGF restrained glycolytic metabolism by downregulating the expression of HK2, p-PKM2, and LDHA and by reducing pyruvate and lactate production. Besides, SGF mitigated AIM2 inflammasome activation and decreased the levels of AIM2, ASC, caspase-1, and IL-1β. Mechanistic validation confirmed that PKM2 was abundantly expressed in macrophages, and PKM2 overexpression partially abrogated the inhibitory effects of SGF on glycolysis and AIM2 inflammasome signaling. Co-culture assays further demonstrated that PKM2 overexpression in RAW264.7 macrophages exacerbated lipid deposition, oxidative stress, glycolysis, and AIM2 inflammasome activation in AML-12 hepatocytes, thereby counteracting the hepatoprotective effects of SGF. Conclusion SGF effectively ameliorates HFD-induced NASH by reversing metabolic disturbance, relieving oxidative stress and liver injury, and suppressing PKM2-dependent glycolysis and AIM2 inflammasome activation. Macrophage PKM2 acts as a key mediator of pathogenic macrophage-hepatocyte crosstalk, which is critical for the hepatoprotective effects of SGF against NASH. Overall, our study findings highlight SGF as a promising therapeutic option for this specific population.
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