Curcumin analogue FLLL32 induces ferroptosis by targeting the STAT3-GPX4/SLC40A1 axis in colorectal cancer.
4 affiliations
- 1Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, State Key Laboratory of Biotherapy and Cancer Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
- 2Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
- 3Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China. [email protected].
- 4Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, State Key Laboratory of Biotherapy and Cancer Center, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
Abstract
FLLL32 is a curcumin analogue with reported anti-tumor activity, mainly through inhibition of signal transducer and activator of transcription 3 (STAT3) signaling and induction of apoptosis. However, whether FLLL32 regulates ferroptosis in colorectal cancer (CRC) and the underlying mechanism remain unclear. Here, using a patient-derived CRC organoid screening platform, we identified FLLL32 as a potent anti-CRC compound. FLLL32 suppressed CRC organoid growth, inhibited CRC cell proliferation and migration in vitro, and inhibited xenograft tumor growth in vivo. In parallel, FLLL32 induced ferroptosis-associated iron accumulation, reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial morphological and functional abnormalities. The ferroptosis inhibitor Ferrostatin-1 markedly restored FLLL32-impaired cell viability and reduced ROS, whereas the apoptosis inhibitor Z-VAD-FMK showed weaker protection. These findings suggest that ferroptosis is a major contributor to FLLL32-induced cell death, although apoptotic features are also present. Mechanistically, FLLL32 interacted with STAT3, and Glu638 and Met726 contributed to the FLLL32-STAT3 interaction. FLLL32 also suppressed STAT3 Tyr705 phosphorylation and nuclear signaling, thereby disrupting pSTAT3-mediated transcriptional regulation of glutathione peroxidase 4 (GPX4) and solute carrier family 40 member 1 (SLC40A1), weakening lipid peroxide detoxification and cellular iron efflux, promoting intracellular iron accumulation, and enhancing ferroptosis in CRC cells. These findings define a STAT3-GPX4/SLC40A1-dependent mechanism underlying the anti-CRC activity of FLLL32 and support further investigation of STAT3-associated ferroptosis regulation as a potential therapeutic vulnerability in CRC.
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BibTeX
@article{wu2026curcumin,
title = {{Curcumin analogue FLLL32 induces ferroptosis by targeting the STAT3-GPX4/SLC40A1 axis in colorectal cancer.}},
author = {Tong Wu and Mengqiu Hao and Qiuye Luo and Sicheng Liu and Yaguang Zhang and Yang Zhang and Xuyang Yang and Junhong Han},
journal = {Molecular biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00575-5},
url = {https://europepmc.org/article/MED/42900324},
note = {CC BY},
}
RIS
TY - JOUR
TI - Curcumin analogue FLLL32 induces ferroptosis by targeting the STAT3-GPX4/SLC40A1 axis in colorectal cancer.
AU - Tong Wu
AU - Mengqiu Hao
AU - Qiuye Luo
AU - Sicheng Liu
AU - Yaguang Zhang
AU - Yang Zhang
AU - Xuyang Yang
AU - Junhong Han
PY - 2026
DA - 2026/10/20
JO - Molecular biomedicine
DO - 10.1186/s43556-026-00575-5
UR - https://europepmc.org/article/MED/42900324
AB - FLLL32 is a curcumin analogue with reported anti-tumor activity, mainly through inhibition of signal transducer and activator of transcription 3 (STAT3) signaling and induction of apoptosis. However, whether FLLL32 regulates ferroptosis in colorectal cancer (CRC) and the underlying mechanism remain unclear. Here, using a patient-derived CRC organoid screening platform, we identified FLLL32 as a potent anti-CRC compound. FLLL32 suppressed CRC organoid growth, inhibited CRC cell proliferation and migration in vitro, and inhibited xenograft tumor growth in vivo. In parallel, FLLL32 induced ferroptosis-associated iron accumulation, reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial morphological and functional abnormalities. The ferroptosis inhibitor Ferrostatin-1 markedly restored FLLL32-impaired cell viability and reduced ROS, whereas the apoptosis inhibitor Z-VAD-FMK showed weaker protection. These findings suggest that ferroptosis is a major contributor to FLLL32-induced cell death, although apoptotic features are also present. Mechanistically, FLLL32 interacted with STAT3, and Glu638 and Met726 contributed to the FLLL32-STAT3 interaction. FLLL32 also suppressed STAT3 Tyr705 phosphorylation and nuclear signaling, thereby disrupting pSTAT3-mediated transcriptional regulation of glutathione peroxidase 4 (GPX4) and solute carrier family 40 member 1 (SLC40A1), weakening lipid peroxide detoxification and cellular iron efflux, promoting intracellular iron accumulation, and enhancing ferroptosis in CRC cells. These findings define a STAT3-GPX4/SLC40A1-dependent mechanism underlying the anti-CRC activity of FLLL32 and support further investigation of STAT3-associated ferroptosis regulation as a potential therapeutic vulnerability in CRC.
SN - 2662-8651
ER -