Targeting PIP5K ameliorates hepatic cancer by inhibiting PI3K/AKT and the autophagy mechanism and enhancing ROS-mediated apoptosis

作者：P. A. Shantanu, Bishal Rajdev, N.P. Syamprasad, Jagadeesh Kumar Gangasani, Arijit Mandal, Samir Ranjan Panda, Ramakrishna Sistla, Sai Balaji Andugulapati, Shiv Kumar Sarin, Dinesh Mani Tripathi, V. G. M. Naidu · 发表于：Frontiers in Pharmacology · 年份：2026 · DOI：10.3389/fphar.2026.1791462 · 被引用次数：1 · 研究领域：Genomics, phytochemicals, and oxidative stress、Autophagy in Disease and Therapy、PI3K/AKT/mTOR signaling in cancer

Introduction Hepatic cancer cells regulate reactive oxygen species (ROS) and lipid kinases to promote proliferation and survival. The role of phosphatidylinositol-4-phosphate-5-kinase (PIP5K) in modulating the autophagy–Nrf2 antioxidant pathway remains unclear. In this study, we investigated the impact of PIP5K on the ROS-dependent autophagy–Nrf2 axis using specific isoform inhibitors (PIP5K1A: ISA-201IB; PIP5K1B: IITZ01) and further identified NG-TZ-17 and NG-TZ-20, which are analogs of IITZ01, as novel inhibitors of the PIP5KB isoform. Methods The association between PIP5K and the ROS–autophagy–Nrf2 pathway was examined in hepatocellular carcinoma (HCC) tissue samples (n = 36) and hepatic cancer cell lines. In vitro , HepG2 cells (expressing high PIP5K levels) were treated with PIP5K isoform-specific inhibitors, autophagy inhibitors, and Nrf2 inhibitors in the presence of hydrogen peroxide (H 2 O 2 ). The effects on ROS generation, proliferation, autophagy, antioxidant defense, and apoptosis were assessed using MitoSOX staining, immunofluorescence, and Western blot analysis. In vivo , SCID mice xenografted with GFP-HepG2 cells were treated orally with PIP5K inhibitors (IITZ01 and NG-TZ-17; 50 mg/kg) or sorafenib (60 mg/kg). Tumor progression was monitored through animal imaging, survival analysis, tumor volume measurement, and Western blotting of excised tumors. Results PIP5K isoforms, Beclin-1, and Nrf2 expression increased with advancing HCC grade. Autophagy induction upr...