Scutellarin suppresses Mycobacterium tuberculosis-induced pyroptosis in macrophages by inhibiting the HIF-1α-mediated Warburg effect

  • Redox Rep. 2025 Dec;30(1):2565861. doi: 10.1080/13510002.2025.2565861.
Jianchao Wu  1 ,  Fanglin Liu  1 ,  Jingjing Shen  1 ,  Hemin Zhang  1 ,  Yaqi Liu  1 ,  Jinxia Sun  1 ,  Guizhen Yang  1 ,  Yuejuan Zheng  2  3 ,  Xin Jiang  1  2
Affiliations
  • 1. Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.
  • 2. The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.
  • 3. School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.
PMID: 41051976 DOI: 10.1080/13510002.2025.2565861
Abstract

Background: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a major global health threat due to prolonged treatment and drug-resistant strains. Host-directed therapy (HDT), which modulates host-pathogen interactions, offers potential to shorten treatment and limit resistance. This study investigates the effects of Scutellarin (SCU), a flavonoid from Scutellaria baicalensis, on Mtb-infected macrophages within the HDT framework.

Methods: Anti-pyroptotic and anti-inflammatory effects of SCU were assessed in Mtb-infected THP-1 and J774A.1 macrophages, and in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. Mitochondrial function was evaluated by oxygen consumption rate(OCR), membrane potential, and superoxide levels; glycolytic activity was measured by proton efflux rate (GlycoPER). Expression of inflammasome-related markers was analyzed by Western blot, qPCR, ELISA, immunofluorescence, and flow cytometry. The role of hypoxia-inducible factor 1-alpha (HIF-1α) was examined via siRNA knockdown.

Results: SCU inhibited NLRP3 inflammasome activation, reduced IL-1β and IL-18 secretion, and attenuating Pyroptosis. It restored mitochondrial integrity by regulating p-DRP1, MFN2, and Cytochrome C expression, and suppressed HIF-1α-mediated glycolytic reprogramming. Silencing of HIF-1α confirmed its role in SCU's mechanism. In vivo, SCU reduced pulmonary inflammation and cytokine release in LPS-induced ALI.

Conclusion: SCU alleviates Mtb-induced Pyroptosis and inflammation in macrophages by inhibiting the HIF-1α-mediated Warburg effect.

Keywords
Mitochondrial dysfunction; Mycobacterium tuberculosis; NLRP3 inflammasome; Pyroptosis; Scutellarin; Warburg effect; host-directed therapy; hypoxia-inducible factor-1α.
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