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Background <p>Sunitinib is an important therapeutic option for renal cell carcinoma (RCC), but reduced response to sunitinib still limits its clinical benefit. This study explored the mechanism underlying reduced sunitinib sensitivity in RCC and aimed to identify potential strategies to improve sunitinib response.</p> Methods <p>RCC organoids were established and characterized, and sunitinib-responsive genes were screened by transcriptomic analysis. Public datasets and clinical RCC samples were used to evaluate the clinical relevance of ALDH1L2. ALDH1L2 overexpression and knockdown were performed in RCC organoids to examine its effects on sunitinib sensitivity and ferroptosis-related changes. Organoid-derived xenograft models were used for in vivo validation. Molecular docking, cytotoxicity assays, CETSA, SPR, and functional experiments were used to screen and validate candidate compounds targeting ALDH1L2.</p> Results <p>Sunitinib inhibited RCC organoid growth, with IC50 values of approximately 8 μM. Transcriptomic analysis showed that ALDH1L2 was upregulated after sunitinib treatment. Clinical analyses indicated that ALDH1L2 was highly expressed in RCC tissues and was associated with poorer survival and advanced stage. In RCC organoids, ALDH1L2 overexpression attenuated sunitinib-induced ROS accumulation and ferroptosis-related changes, as reflected by changes in GPX4, SLC7A11, GSH/GSSG, NADP<sup>+</sup> /NADPH, Fe<sup>2 +</sup>, and MDA. In contrast, ALDH1L2 knockdown enhanced these changes and increased the sensitivity of RCC organoids to sunitinib. In organoid-derived xenograft models, ALDH1L2 overexpression reduced the antitumor effect of sunitinib and decreased tumor ROS accumulation. Erastin counteracted the protective effect of ALDH1L2 overexpression. Hederacolchiside A1 (HA-1) was identified as a candidate compound targeting ALDH1L2. HA-1 reduced ALDH1L2 protein abundance, altered its thermal stability, enhanced the inhibitory effect of sunitinib, and counteracted ALDH1L2-mediated sunitinib tolerance in RCC organoids.</p> Conclusions <p>These findings suggest that ALDH1L2 contributes to reduced sunitinib sensitivity in RCC organoids by attenuating ferroptosis-related responses. HA-1 may improve the response of RCC organoids to sunitinib by targeting ALDH1L2, supporting further evaluation of this combination strategy.</p>

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ALDH1L2 suppresses ferroptosis-associated responses and reduces sunitinib sensitivity in renal cell carcinoma organoids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • Xinming Hu,
  • Jie Yang,
  • Desheng Li,
  • Meizhou Deng,
  • Mei Xie,
  • Jiangtao Zhan,
  • Changmin Yang,
  • Xianping Che,
  • Kangli Deng

摘要

Background

Sunitinib is an important therapeutic option for renal cell carcinoma (RCC), but reduced response to sunitinib still limits its clinical benefit. This study explored the mechanism underlying reduced sunitinib sensitivity in RCC and aimed to identify potential strategies to improve sunitinib response.

Methods

RCC organoids were established and characterized, and sunitinib-responsive genes were screened by transcriptomic analysis. Public datasets and clinical RCC samples were used to evaluate the clinical relevance of ALDH1L2. ALDH1L2 overexpression and knockdown were performed in RCC organoids to examine its effects on sunitinib sensitivity and ferroptosis-related changes. Organoid-derived xenograft models were used for in vivo validation. Molecular docking, cytotoxicity assays, CETSA, SPR, and functional experiments were used to screen and validate candidate compounds targeting ALDH1L2.

Results

Sunitinib inhibited RCC organoid growth, with IC50 values of approximately 8 μM. Transcriptomic analysis showed that ALDH1L2 was upregulated after sunitinib treatment. Clinical analyses indicated that ALDH1L2 was highly expressed in RCC tissues and was associated with poorer survival and advanced stage. In RCC organoids, ALDH1L2 overexpression attenuated sunitinib-induced ROS accumulation and ferroptosis-related changes, as reflected by changes in GPX4, SLC7A11, GSH/GSSG, NADP+ /NADPH, Fe2 +, and MDA. In contrast, ALDH1L2 knockdown enhanced these changes and increased the sensitivity of RCC organoids to sunitinib. In organoid-derived xenograft models, ALDH1L2 overexpression reduced the antitumor effect of sunitinib and decreased tumor ROS accumulation. Erastin counteracted the protective effect of ALDH1L2 overexpression. Hederacolchiside A1 (HA-1) was identified as a candidate compound targeting ALDH1L2. HA-1 reduced ALDH1L2 protein abundance, altered its thermal stability, enhanced the inhibitory effect of sunitinib, and counteracted ALDH1L2-mediated sunitinib tolerance in RCC organoids.

Conclusions

These findings suggest that ALDH1L2 contributes to reduced sunitinib sensitivity in RCC organoids by attenuating ferroptosis-related responses. HA-1 may improve the response of RCC organoids to sunitinib by targeting ALDH1L2, supporting further evaluation of this combination strategy.