HIF-1α translation mediated by PKCδ facilitates RSV-induced production of innate inflammatory cytokines in vitro and in vivo

  • Free Radic Biol Med. 2026 Mar 16:246:614-626. doi: 10.1016/j.freeradbiomed.2026.01.049.
Lifeng Chen  1 ,  Jiayi Chen  2 ,  Chuyi Liao  3 ,  Bin Chen  2 ,  Jiahua Zou  3 ,  Yujun Tang  3 ,  Si Xiong  4 ,  Zhong Liu  5 ,  Manmei Li  6
Affiliations
  • 1. Department of Biochemistry & School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China.
  • 2. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China.
  • 3. Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
  • 4. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China. Electronic address: [email protected].
  • 5. Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China. Electronic address: [email protected].
PMID: 41611036 DOI: 10.1016/j.freeradbiomed.2026.01.049
Abstract

A cytokine storm caused by respiratory syncytial virus (RSV) significantly influences the progression of pneumonia and bronchiolitis. It is essential to comprehend the underlying mechanism of the RSV-triggered cytokine storm to effectively manage RSV. Hypoxia-inducible factor-1 Alpha (HIF-1α) plays a pivotal role in innate immunity. It is known that RSV enhances HIF-1α expression, but the molecular mechanism of RSV-induced HIF-1α expression and its role in the production of innate inflammatory cytokines during RSV Infection are not fully understood. Our research demonstrates that RSV Infection increases HIF-1α expression both in vitro and in vivo. Further investigation into the mechanism of RSV-induced HIF-1α expression indicates that PKCδ regulates RSV-induced HIF-1α translation through the PI3K/Akt/mTOR signaling pathway. Additionally, HIF-1α expression, mediated by PKCδ/PI3K/Akt/mTOR signaling, stimulates the production of innate inflammatory cytokines by activating the NLRP3-inflammasome during RSV Infection. Inhibition of HIF-1α or PKCδ markedly suppresses RSV-induced inflammation in vitro and in vivo. In summary, these findings elucidate the molecular mechanism of RSV-induced HIF-1α expression and identify HIF-1α as a novel target for anti-RSV drug development.

Keywords
HIF-1α; Innate inflammatory cytokines; PKCδ; Respiratory syncytial virus.
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