PKC activators improve the function of biogenesis-deficient CFTR channels

  • Mol Ther. 2026 Jul 1;34(7):4212-4225. doi: 10.1016/j.ymthe.2026.03.033.
Shi-Wei Ye  1 ,  Xi-Juan Liu  2 ,  Xin-Lei Kang  3 ,  Li Shen  4 ,  Shi-Qing Cai  5
Affiliations
  • 1. University of Shanghai for Science and Technology (USST), Oriental Pan-Vascular Devices Innovation College, Shanghai 200093, China; Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; Department of Clinical Laboratory, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China.
  • 3. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
  • 4. University of Shanghai for Science and Technology (USST), Oriental Pan-Vascular Devices Innovation College, Shanghai 200093, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Ischemic Heart Diseases, Shanghai 200032, China. Electronic address: [email protected].
  • 5. Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; Department of Clinical Laboratory, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; Department of Anesthesiology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Key Laboratory of Anesthesiology, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: [email protected].
PMID: 41925277 DOI: 10.1016/j.ymthe.2026.03.033
Abstract

Cystic fibrosis (CF) is a lethal genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most prevalent disease-causing mutation, F508del, results in the production of misfolded CFTR proteins, which are prematurely degraded. Given the complex pathology of CF, a multimodal therapeutic strategy is essential. This underscores the urgent need to develop adjunctive modulators that synergize with existing therapies. Here, we show that protein kinase C (PKC) activators ingenol-3,20-dibenzoate and 12-deoxyphorbol 13-phenylacetate 20-acetate enhance F508del-CFTR channel function through a mechanism distinct from that of currently FDA-approved CFTR correctors. These agents enhance F508del-CFTR function as monotherapies; in combination with CFTR correctors, they largely restore the channel function in both immortalized human airway epithelial cells and CFTRF508del/F508del mouse lungs. Notably, they also attenuate CFTRF508del/F508del mouse pulmonary inflammation induced by Infection. Furthermore, PKC activators enhance the function of CFTR harboring rare missense mutations that are refractory to existing therapies. Mechanistically, PKCε-mediated phosphorylation of nascent CFTR stabilizes the translating CFTR transcripts, thereby promoting channel synthesis. These findings reveal a previously unappreciated role of PKCε signaling in CFTR biogenesis and suggest a potential combinatorial treatment strategy to achieve a more complete functional rescue of mutant CFTR.

Keywords
CFTR; PKC activator; biogenesis; cystic fibrosis; mRNA stability; phosphorylation.
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