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Peer-reviewedCC BY-NC-NDBiology direct

The YTHDF1/CAV1 axis regulates clear cell renal cell carcinoma progression through ferroptosis and apoptosis.

  • Yulin Sun1,2
  • Songbo Wang3
  • Jinpeng Sun1
  • Shouwei Zhu1
  • Huanmin Lou4
  • Da Gu5
  • Shancheng Ren6,7
  • Zilian Cui8
  • Weiting Kang9
9 affiliations
  1. 1Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
  2. 2Department of Urology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
  3. 3Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, China.
  4. 4Department of Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250013, China.
  5. 5Department of Plastic Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250013, China. [email protected].
  6. 6Department of Urology, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, China. [email protected].
  7. 7Department of Urology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China. [email protected].
  8. 8Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China. [email protected].
  9. 9Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China. [email protected].
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Abstract

Background

Sorafenib exerts antitumor activity in clear cell renal cell carcinoma (ccRCC), but its precise mechanisms involving regulated cell death remain incompletely understood. Ferroptosis has emerged as an important effector of sorafenib-mediated antitumor activity; however, the regulatory network controlling ferroptosis in ccRCC, particularly the role of epitranscriptomic regulators such as the N6-methyladenosine reader YTHDF1, remains poorly defined.Results

Sorafenib induced ferroptosis in ccRCC cells, as evidenced by increased intracellular ferrous iron, reactive oxygen species, lipid peroxides, and malondialdehyde levels, and was accompanied by reduced YTHDF1 expression. Genetic silencing of YTHDF1 robustly activated both ferroptosis and apoptosis, characterized by iron accumulation, oxidative stress, lipid peroxidation, mitochondrial damage, an increased Bax/Bcl-2 ratio, Caspase-3 activation, and PARP1 cleavage. These changes significantly suppressed ccRCC cell proliferation, migration, and invasion. Integrated RNA sequencing and RIP sequencing analyses, together with molecular validation, identified Caveolin-1 (CAV1) as a downstream target of YTHDF1. Rescue experiments showed that CAV1 overexpression effectively reversed the ferroptotic and apoptotic phenotypes, as well as the impaired malignant behaviors, induced by YTHDF1 knockdown. In vivo, YTHDF1 depletion markedly inhibited xenograft tumor growth, whereas restoration of CAV1 reversed this tumor-suppressive effect and attenuated the associated ferroptosis- and apoptosis-related changes.Conclusions

This study identifies the YTHDF1/CAV1 signaling axis as a critical regulator that concurrently suppresses ferroptosis and apoptosis in ccRCC, highlighting it as a promising therapeutic target to inhibit ccRCC progression.

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Cite

BibTeXRIS
BibTeX
@article{sun2026ythdf1cav1,
  title = {{The YTHDF1/CAV1 axis regulates clear cell renal cell carcinoma progression through ferroptosis and apoptosis.}},
  author = {Yulin Sun and Songbo Wang and Jinpeng Sun and Shouwei Zhu and Huanmin Lou and Da Gu and Shancheng Ren and Zilian Cui and Weiting Kang},
  journal = {Biology direct},
  year = {2026},
  month = aug,
  doi = {10.1186/s13062-026-00939-5},
  url = {https://europepmc.org/article/MED/43010063},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - The YTHDF1/CAV1 axis regulates clear cell renal cell carcinoma progression through ferroptosis and apoptosis.
AU  - Yulin Sun
AU  - Songbo Wang
AU  - Jinpeng Sun
AU  - Shouwei Zhu
AU  - Huanmin Lou
AU  - Da Gu
AU  - Shancheng Ren
AU  - Zilian Cui
AU  - Weiting Kang
PY  - 2026
DA  - 2026/08/13
JO  - Biology direct
DO  - 10.1186/s13062-026-00939-5
UR  - https://europepmc.org/article/MED/43010063
AB  - Background  Sorafenib exerts antitumor activity in clear cell renal cell carcinoma (ccRCC), but its precise mechanisms involving regulated cell death remain incompletely understood. Ferroptosis has emerged as an important effector of sorafenib-mediated antitumor activity; however, the regulatory network controlling ferroptosis in ccRCC, particularly the role of epitranscriptomic regulators such as the N6-methyladenosine reader YTHDF1, remains poorly defined.Results  Sorafenib induced ferroptosis in ccRCC cells, as evidenced by increased intracellular ferrous iron, reactive oxygen species, lipid peroxides, and malondialdehyde levels, and was accompanied by reduced YTHDF1 expression. Genetic silencing of YTHDF1 robustly activated both ferroptosis and apoptosis, characterized by iron accumulation, oxidative stress, lipid peroxidation, mitochondrial damage, an increased Bax/Bcl-2 ratio, Caspase-3 activation, and PARP1 cleavage. These changes significantly suppressed ccRCC cell proliferation, migration, and invasion. Integrated RNA sequencing and RIP sequencing analyses, together with molecular validation, identified Caveolin-1 (CAV1) as a downstream target of YTHDF1. Rescue experiments showed that CAV1 overexpression effectively reversed the ferroptotic and apoptotic phenotypes, as well as the impaired malignant behaviors, induced by YTHDF1 knockdown. In vivo, YTHDF1 depletion markedly inhibited xenograft tumor growth, whereas restoration of CAV1 reversed this tumor-suppressive effect and attenuated the associated ferroptosis- and apoptosis-related changes.Conclusions  This study identifies the YTHDF1/CAV1 signaling axis as a critical regulator that concurrently suppresses ferroptosis and apoptosis in ccRCC, highlighting it as a promising therapeutic target to inhibit ccRCC progression.
SN  - 1745-6150
ER  -