Resveratrol combats Salmonella infection via liberating vacuole-enclosed bacteria for enhanced autophagic clearance and blocking HMGA2-mediated G2/M arrest

  • Phytomedicine. 2026 May:154:158042. doi: 10.1016/j.phymed.2026.158042.
Jiayang Liu  1 ,  Xueyu Li  1 ,  Jinli Ge  1 ,  Qian Li  1 ,  Jiaqi Fu  2 ,  Hua Ye  2 ,  Hongtao Liu  1 ,  Jianfeng Wang  1 ,  Xuming Deng  1 ,  Youzhi Tang  3 ,  Kui Zhu  4 ,  Jiazhang Qiu  5
Affiliations
  • 1. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062 China.
  • 2. Department of Respiratory Medicine, Center of Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of The Ministry of Education, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, The First Hospital of Jilin University, Changchun 130021, China.
  • 3. Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agriculture University, Guangzhou, Guangdong 510642, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. Electronic address: [email protected].
  • 5. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062 China. Electronic address: [email protected].
PMID: 41812383 DOI: 10.1016/j.phymed.2026.158042
Abstract

The escalating crisis of antimicrobial resistance necessitates a paradigm shift toward host-directed therapies (HDTs) that circumvent pathogen evasion strategies. Here we show that the natural polyphenol resveratrol clears intracellular Salmonella typhimurium (S. typhimurium) by orchestrating a multipronged strategy involving Salmonella-containing vacuole (SCV) disruption via ERK1/2 inhibition to liberate bacteria for enhanced autophagic clearance, concurrently reversing pathogen-induced G2/M cell cycle arrest. We identify High Mobility Group AT-Hook 2 (HMGA2) as a critical, previously unrecognized host dependency factor essential for Salmonella-driven cell cycle manipulation, which resveratrol targets to restrict Bacterial replication. Furthermore, we characterize a resveratrol derivative, RV15, with enhanced potency and a distinct target profile validated by cellular thermal shift assay and proteome-wide reverse docking. This work underscores the potential of multipronged host modulation to eliminate intracellular pathogens that evade conventional Antibiotics.

Keywords
Autophagy; Cell cycle; ERK1/2; Host-directed therapy; Resveratrol; Salmonella.
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