2. Academic Validation
  3. FAT4 loss promotes tumor growth and ferroptosis resistance in hepatocellular carcinoma via PI3K/AKT pathway activation

FAT4 loss promotes tumor growth and ferroptosis resistance in hepatocellular carcinoma via PI3K/AKT pathway activation

  • Clin Transl Oncol. 2026 Mar 14. doi: 10.1007/s12094-026-04302-y.
Jing Li # 1 2,  Jialing Sun # 1 2,  Rui Hu # 1 2,  Mengqing Ma 1 2,  Kongli Fan 1 2,  Minling Lv 1 2,  Qi Huang 1 2,  Wenmin Yang 1 2,  Yuan Yang 1 2,  Yan Wang 1 2,  Xiaozhou Zhou 1 2,  Xinfeng Sun 3 4
Affiliations

Affiliations

  • 1 Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, 1 Fuhua Road, Futian, Shenzhen, 518033, Guangdong, China.
  • 2 Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China.
  • 3 Department of Liver Disease, Shenzhen Traditional Chinese Medicine Hospital, 1 Fuhua Road, Futian, Shenzhen, 518033, Guangdong, China. [email protected].
  • 4 Department of Liver Disease, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China. [email protected].
  • # Contributed equally.
PMID: 41832339 DOI: 10.1007/s12094-026-04302-y
Abstract

Purpose: Drug resistance in hepatocellular carcinoma (HCC) presents a substantial therapeutic challenge. Ferroptosis has emerged as a promising therapeutic strategy, yet the mechanisms underlying resistance are not fully elucidated. Here, we highlight the tumor suppressor FAT4 as a crucial regulator of Ferroptosis sensitivity in HCC.

Methods: We examined the role of FAT4 in Ferroptosis in HCC using a combination of bioinformatics analysis, experiments on tissue samples from patients with HCC, and a subcutaneous xenograft tumor model in nude mice.

Results: FAT4 expression was significantly downregulated in HCC tissues, and this downregulation correlated with poor patient survival. Functionally, FAT4 loss promoted tumor growth and resistance to Ferroptosis inducers (RSL3 and sorafenib), evidenced by reduced lipid peroxidation and increased levels of GPX4 and SLC7A11. Mechanistically, FAT4 deficiency was associated with activation of the PI3K/Akt signaling pathway. Notably, pharmacological inhibition of PI3K/Akt restored Ferroptosis sensitivity and resensitized FAT4-deficient HCC cells to sorafenib.

Conclusions: FAT4 may enhance Ferroptosis sensitivity in HCC by suppressing GPX4 and SLC7A11 expression, potentially by inhibiting PI3K/Akt signaling. Thus, this study presents FAT4 as a biomarker associated with tumor progression and a potential determinant for overcoming Ferroptosis resistance in HCC.

Keywords

FAT4; Ferroptosis; Hepatocellular carcinoma; PI3K/AKT; Sorafenib.

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