文献类型：期刊文献

英文题名：Astragaloside IV directly targets PPP1R14B to sensitize prostate cancer to anti-PD-1 immunotherapy by remodeling the CX3CL1/CD8+T cell axis

作者：Yang, Jie[1];Wang, Jia[2];Zhang, Wenbo[2];He, Han[1];Wang, Chao[1];Zhang, Yunfeng[1];Zhou, Fenghai[1,2,3]

第一作者：Yang, Jie

通信作者：Zhou, FH[1];Zhou, FH[2];Zhou, FH[3]

机构：[1]Lanzhou Univ, Sch Clin Med 1, Lanzhou 730000, Gansu, Peoples R China;[2]Gansu Univ Chinese Med, Clin Med Coll 1, Lanzhou 730000, Gansu, Peoples R China;[3]Gansu Prov Hosp, Dept Urol, Lanzhou 730000, Gansu, Peoples R China

第一机构：Lanzhou Univ, Sch Clin Med 1, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Sch Clin Med 1, Lanzhou 730000, Gansu, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Clin Med Coll 1, Lanzhou 730000, Gansu, Peoples R China;[3]corresponding author), Gansu Prov Hosp, Dept Urol, Lanzhou 730000, Gansu, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：155

外文期刊名：PHYTOMEDICINE

收录：;Scopus(收录号：2-s2.0-105034969178);WOS:【SCI-EXPANDED(收录号:WOS:001741402500001)】；

基金：This research was supported by the Natural Science Foundation of Gansu Province "excellent doctoral program" (No. 24JRRA613) , Innovation Fund Project for University Teachers of Gansu Province (2026B-006) and Lanzhou University First Hospital fund (No. ldyyyn2023-33) .

语种：英文

外文关键词：Prostate cancer; Astragaloside IV; Immune exclusion; Wnt/beta-catenin signaling; CX3CL1

摘要：Background: Resistance to immune checkpoint inhibitors (ICIs) in prostate cancer (PCa) is driven by a "cold" tumor immune microenvironment. Astragaloside IV (AS-IV), a major bioactive saponin isolated from Astragalus membranaceus, exhibits immunomodulatory potential, yet its direct molecular targets remain elusive. Concurrently, PPP1R14B is overexpressed in PCa, but its role in mediating immune evasion is unclear. Purpose: To investigate whether AS-IV targets PPP1R14B to remodel the tumor immune microenvironment (TIME) and sensitize PCa to anti-PD-1 therapy. Methods: The AS-IV/PPP1R14B interaction was validated using molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assays (CETSA). Mechanisms were dissected via ubiquitination assays, ROS analysis, and T cell co-cultures. Antitumor efficacy was evaluated in syngeneic mouse models alone or with anti-PD-1. Results: AS-IV bound PPP1R14B (KD = 4.88 & micro;M), inducing its ubiquitin-proteasomal degradation. This depletion inhibited Wnt/(3-catenin signaling via regulation of the AKT/GSK-3(3 axis and induction of mitochondrial ROS. Consequently, AS-IV relieved CX3CL1 repression, promoting the recruitment and cytotoxic function of CD8+ T cells. In vivo, AS-IV synergized with anti-PD-1 to suppress tumor growth, an effect that was largely dependent on PPP1R14B downregulation. Conclusion: AS-IV reverses immune exclusion by targeting PPP1R14B to suppress Wnt/(3-catenin signaling. These findings identify the AS-IV/PPP1R14B/CX3CL1 axis as a mechanistic basis for using AS-IV to overcome ICI resistance in PCa.