Tubacin induces TFEB-dependent ferritinophagy independently of HDAC6 and sensitizes cancer cells to ferroptosis under GSH-GPX4 axis disruption.

Authors

Gyeongmi Kim, Se-Kyeong Jang, Do-Gyeong Kim, Hyunggee Kim, Jae Ho Lee, Seunghee Bae, In-Chul Park, Hyeon-Ok Jin

Published in

Biochemical pharmacology. Pages 118458. Sep 10, 2026. Epub Sep 10, 2026.

Abstract

Histone deacetylase 6 (HDAC6) is a promising therapeutic target in cancer. However, its inhibitors show limited efficacy as monotherapies and are more effective in combination settings, suggesting a context-dependent mechanism that remains poorly defined. Here, we show that tubacin sensitizes cancer cells to ferroptosis under glutathione (GSH) depletion caused by buthionine sulfoximine (BSO). This effect was not observed with other HDAC6 inhibitors or with HDAC6 depletion, suggesting a mechanism not solely attributable to HDAC6 inhibition. Co-treatment with tubacin and BSO induced lipid peroxidation, which was abrogated by ferroptosis inhibitors, indicating ferroptosis as the predominant mode of cell death. Mechanistically, tubacin activated transcription factor EB (TFEB), leading to lysosomal acidification and expansion, accompanied by ferritin degradation and increased intracellular ferrous iron. These effects were reversed by TFEB silencing, lysosomal inhibition, or nuclear receptor coactivator 4 depletion, supporting a role for TFEB-dependent lysosomal ferritinophagy. However, iron accumulation driven by tubacin was insufficient to trigger ferroptosis, indicating a requirement for redox imbalance. Consistently, tubacin enhanced ferroptosis under GSH-glutathione peroxidase 4 (GPX4) axis disruption by imidazole ketone erastin or arsenic trioxide. Collectively, our findings identify TFEB-driven lysosomal activation and ferritinophagy as a critical determinant of ferroptotic sensitivity under redox imbalance and suggest that pharmacological modulation of TFEB-lysosomal function by tubacin may represent a potential strategy for enhancing ferroptosis-based cancer therapy.

PMID:
42722085
Bibliographic data and abstract were imported from PubMed on 11 Sep 2026.

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