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TSC22D4 drives clear cell renal cell carcinoma progression and therapy resistance by stabilizing NRF2 through KEAP1

Bohan Zeng1,2, Songbo Wang3, Xuanzhi Zhang2

  • 1Department of Urology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China.

Cell Death & Disease
|June 5, 2026
PubMed

Insights

TSC22D4 promotes aggressive kidney cancer (ccRCC) by stabilizing the NRF2 protein, leading to resistance against oxidative stress and ferroptosis. This discovery identifies TSC22D4 as a potential therapeutic target for ccRCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer known for its resistance to oxidative stress.
  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of oxidative stress responses, frequently overexpressed in ccRCC and linked to poor prognosis.

Purpose of the Study:

  • To identify upstream regulators of NRF2 stability in ccRCC.
  • To investigate the role of TSC22D4 in ccRCC progression and resistance to therapy.

Main Methods:

  • Identified TSC22D4 as a KEAP1-interacting protein using its ETGE motif.
  • Assessed the impact of TSC22D4 on the KEAP1-NRF2 complex and NRF2 transcriptional activity.
  • Evaluated TSC22D4's effect on ferroptosis, sorafenib resistance, and ccRCC cell proliferation, invasion, and metastasis in vitro and in vivo.

Main Results:

  • TSC22D4 directly binds to KEAP1, disrupting the KEAP1-NRF2 complex and stabilizing NRF2.
  • TSC22D4 upregulates SLC7A11, suppressing ferroptosis and conferring resistance to sorafenib in ccRCC.
  • Overexpression of TSC22D4 in ccRCC correlates with advanced disease stage and reduced patient survival.

Conclusions:

  • TSC22D4 promotes ccRCC progression and sorafenib resistance by activating the KEAP1-NRF2-SLC7A11 pathway and inhibiting ferroptosis.
  • TSC22D4 represents a promising therapeutic target for managing ccRCC and overcoming treatment resistance.

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