2. Academic Validation
  3. Scap stabilizes PKM2 to promote glycolysis and enhance anti-fungal immunity in macrophages

Scap stabilizes PKM2 to promote glycolysis and enhance anti-fungal immunity in macrophages

  • Cell Rep. 2026 Mar 24;45(3):117106. doi: 10.1016/j.celrep.2026.117106.
Jiaqi Huang 1,  Yuejue Wang 1,  Fei Li 1,  Nan Zhang 2,  Guoxiong Tian 3,  Dongyu Guo 1,  Yanqi Guo 1,  Zhengyuan Liu 1,  Yinfang Wu 1,  Xiaoping Li 4,  Fei Xu 5,  Zhongnan Qin 1,  Ruixin Jia 1,  Lingling Dong 1,  Shenwei Gao 1,  Jinkang Yu 1,  Jian Lou 1,  Songmin Ying 6,  Daniel H Scharf 2,  Wen Li 7,  Zhihua Chen 8
Affiliations

Affiliations

  • 1 Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
  • 2 Department of Microbiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China; The Fourth Affiliated Hospital, International School of Medicine, Zhejiang University School of Medicine, Yiwu, China.
  • 3 Department of Pharmacy, Center for Regeneration and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Yiwu, China.
  • 4 Department of Laboratory Medicine, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
  • 5 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
  • 6 Department of Pharmacy, Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Zhejiang-Denmark Joint Laboratory of Regeneration and Aging Medicine, Yiwu, China.
  • 7 Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China. Electronic address: [email protected].
  • 8 Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China. Electronic address: [email protected].
PMID: 41831231 DOI: 10.1016/j.celrep.2026.117106
Abstract

Fungal Infection induces substantial but poorly understood metabolic reprogramming in macrophages. We demonstrate that Fungal stimulation reduces Scap levels in human monocytes and murine bone-marrow-derived macrophages (BMDMs), and Scap deficiency impairs cytokine production and phagocytosis, leading to more severe Fungal infections. Although Scap canonically regulates lipid synthesis, pharmacological inhibition of lipid synthesis and genetic ablation of SREBP1/2 reveal that Scap-dependent anti-fungal immunity is largely independent of this pathway. Instead, Scap interacts with and stabilizes PKM2, a key glycolysis enzyme, by competitively inhibiting STUB1-mediated ubiquitination and degradation of PKM2 at Lys-311. PKM2 agonist DASA58 enhances fungus-induced production of pro-inflammatory cytokines and phagocytic activity in wild-type BMDMs and partially rescues these functions in Scap-deficient macrophages, whereas myeloid-specific deletion of PKM2 recapitulates the effects of Scap deficiency. These results identify Scap as a critical regulator of PKM2-mediated glycolysis and demonstrate its potential as a therapeutic target for modulation of anti-fungal immunity.

Keywords

CP: immunology; CP: metabolism; PKM2; STUB1; Scap; anti-fungal immunity; glycolysis; macrophages; phagocytosis; ubiquitination.

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