2. Academic Validation
  3. Kitasamycin overcomes ferroptosis and immunotherapy resistance by targeting the HUWE1-NCOA4-FTH1 axis

Kitasamycin overcomes ferroptosis and immunotherapy resistance by targeting the HUWE1-NCOA4-FTH1 axis

  • Autophagy. 2026 Feb 15:1-19. doi: 10.1080/15548627.2026.2623986.
Daishi Li 1 2 3 4 5 6,  Yating Dian 1 2 3 4 5 6,  Linfeng Li 7,  Songtao Du 8,  Yu Meng 1 2 3 4 5 6,  Lei Yao 9,  Qian Zhou 1 2 3 4 5 6,  Yixiao Xiong 10,  Yuming Sun 11,  Hui Su 1 2 3 4 5 6,  Yayun Li 12,  Ziyu Guo 1 2 3 4 5 6,  Yi Ge 1 2 3 4 5 6,  Sitao Liu 1 2 3 4 5 6,  Furong Zeng 13,  Xiang Chen 1 2 3 4 5 6,  Lixia Lu 1 2 3 4 5 6,  Juan Su 1 2 3 4 5 6,  Guangtong Deng 1 2 3 4 5 6
Affiliations

Affiliations

  • 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
  • 2 National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, China.
  • 3 Hunan Engineering Research Center of Skin Health and Disease, Central South University, Changsha, China.
  • 4 Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China.
  • 5 National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
  • 6 Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China.
  • 7 Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China.
  • 8 Department of Colorectal Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
  • 9 Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, China.
  • 10 Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 11 Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, China.
  • 12 Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, China.
  • 13 Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
PMID: 41612599 DOI: 10.1080/15548627.2026.2623986
Abstract

Clinicians typically avoid Antibiotics use during immunotherapy due to concerns about reduced efficacy. However, Cancer patients requiring Antibiotics postoperatively or for infections urgently need options that provide antimicrobial coverage while potentially enhancing, rather than impairing, immunotherapy. Restoring Ferroptosis susceptibility represents a promising strategy to overcome immunotherapy resistance, yet the role of Antibiotics in modulating Ferroptosis and interacting with immunotherapy remains unexplored. In this study, we screened 96 FDA-approved Antibiotics across seven pharmacological classes and identified the Macrolide kitasamycin as a specific and potent Ferroptosis sensitizer in vitro and in vivo. Mechanistically, kitasamycin competitively bound to HUWE1, inhibiting its E3 ubiquitin Ligase activity, which stabilized NCOA4 and activated the NCOA4-FTH1 ferritinophagy axis. Single-cell transcriptomics, flow cytometry, and multiplex immunohistochemistry revealed that kitasamycin induced immunogenic Ferroptosis and reshaped anti-tumor T-cell immunity. Critically, kitasamycin potentiated immune checkpoint blockade (ICB)-mediated Ferroptosis and overcame ICB resistance across multiple preclinical melanoma models, including B16F10 subcutaneous tumors, BRAF-PTEN-driven spontaneous tumors, and human sourced peripheral blood mononuclear cells (HsPBMCs)-humanized mouse models. Clinically, a high NCOA4, low HUWE1 signature correlated with Ferroptosis activation, increased T-cell infiltration, and improved survival in ICB-treated patients, suggesting its potential as a predictive biomarker. Our findings positioned kitasamycin as a promising adjunct to immunotherapy for Cancer patients requiring concurrent Antibiotic therapy.Abbreviations: FTH1: ferritin heavy chain 1; ICB: immune checkpoint blockade; IFNG: interferon gamma; mIHC: multiplex immunohistochemistry; scRNA-seq: single-cell RNA Sequencing.

Keywords

Antibiotics; ferroptosis; immune checkpoint blockades; immunogenic cell death; immunotherapy; kitasamycin.

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