A Tanshinone IIA Sulfonate Derivative Targets USP21 to Induce SCD1 Degradation, Suppressing NSCLC Metabolism and Enhancing Antitumor Immunity
5 affiliations
- 1Department of Oncology, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
- 2College of Pharmacy, Dalian Medical University, Dalian, China
- 3Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- 4School of Pharmaceutical Engineering and Biotechnology, School of Cosmetics, Zhejiang Pharmaceutical University, No. 666 Siming Road, Ningbo, China
- 5College of Basic Medical Science, Dalian Medical University, Dalian, China
Abstract
Background: The deubiquitinase ubiquitin-specific peptidase 21 (USP21) is a key regulator of tumor metabolism and immune homeostasis in non-small cell lung cancer (NSCLC). Its aberrant activation drives malignant growth, metabolic reprogramming and immune resistance, yet specific USP21 inhibitors for NSCLC therapy remain scarce. We aimed to develop a selective USP21 inhibitor, define its immunometabolic mechanism, and validate its anti-tumor and immunotherapy-sensitizing effects in NSCLC. Methods: We performed structure-based hierarchical virtual screening of a Food and Drug Administration (FDA)-approved drug library, followed by structure-guided optimization to generate USP21-in6. We characterized its USP21 inhibition, cytotoxicity and anti-tumor activity using in vitro NSCLC cell assays and in vivo syngeneic models. Lipidomic profiling and clinical sample analysis were also performed. Results: USP21-in6 potently and preferentially inhibits USP21 (half-maximal inhibitory concentration [IC50] = 0.61 μM; dissociation constant [Kd] = 1.3 μM). These quantitative parameters demonstrate the potent biochemical inhibitory activity of USP21-in6 toward USP21, supporting its suitability for subsequent cellular and in-vivo functional studies. This compound suppresses NSCLC proliferation and induces apoptosis, while exhibiting low toxicity toward normal cells. Mechanistically, USP21 stabilized stearoyl-CoA desaturase 1 (SCD1); USP21-in6 disrupted this USP21-SCD1 axis, triggering SCD1 degradation and blocking fatty acid synthesis. USP21-in6 monotherapy showed robust anti-tumor activity and boosted anti-programmed cell death protein 1 (PD-1) therapy by remodeling the tumor immune microenvironment: it enhanced cluster of differentiation 8-positive (CD8+) T-cell function and destabilized forkhead box protein 3 (Foxp3) to suppress regulatory T cells (Tregs). It lowered SCD1-derived monounsaturated fatty acids (C16:1, C18:1) in tumors and serum. Clinically, co-upregulated USP21 and SCD1 correlated with PD-1 inhibitor resistance. Conclusion: This work identifies USP21 as an important immunometabolic regulator in NSCLC. Targeting USP21 with USP21-in6 supports further investigation of USP21 inhibition as a potential dual strategy to overcome metabolic disorders and immune suppression for NSCLC immunometabolic therapy.
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BibTeX
@article{liu2026tanshinone,
title = {{A Tanshinone IIA Sulfonate Derivative Targets USP21 to Induce SCD1 Degradation, Suppressing NSCLC Metabolism and Enhancing Antitumor Immunity}},
author = {Yang Liu and Lixue Chen and Peng Wang and Xiaoli Ma and Shuaikang Pan and Dafu Yang and Tianyu Zhou and Fang Yu and Jincheng Song and Zhaolin Sun and Zhaoxia Dai and Peng Chu},
journal = {Oncology Research},
year = {2026},
month = oct,
doi = {10.32604/or.2026.089127},
url = {https://doi.org/10.32604/or.2026.089127},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Tanshinone IIA Sulfonate Derivative Targets USP21 to Induce SCD1 Degradation, Suppressing NSCLC Metabolism and Enhancing Antitumor Immunity
AU - Yang Liu
AU - Lixue Chen
AU - Peng Wang
AU - Xiaoli Ma
AU - Shuaikang Pan
AU - Dafu Yang
AU - Tianyu Zhou
AU - Fang Yu
AU - Jincheng Song
AU - Zhaolin Sun
AU - Zhaoxia Dai
AU - Peng Chu
PY - 2026
DA - 2026/10/28
JO - Oncology Research
DO - 10.32604/or.2026.089127
UR - https://doi.org/10.32604/or.2026.089127
AB - Background: The deubiquitinase ubiquitin-specific peptidase 21 (USP21) is a key regulator of tumor metabolism and immune homeostasis in non-small cell lung cancer (NSCLC). Its aberrant activation drives malignant growth, metabolic reprogramming and immune resistance, yet specific USP21 inhibitors for NSCLC therapy remain scarce. We aimed to develop a selective USP21 inhibitor, define its immunometabolic mechanism, and validate its anti-tumor and immunotherapy-sensitizing effects in NSCLC. Methods: We performed structure-based hierarchical virtual screening of a Food and Drug Administration (FDA)-approved drug library, followed by structure-guided optimization to generate USP21-in6. We characterized its USP21 inhibition, cytotoxicity and anti-tumor activity using in vitro NSCLC cell assays and in vivo syngeneic models. Lipidomic profiling and clinical sample analysis were also performed. Results: USP21-in6 potently and preferentially inhibits USP21 (half-maximal inhibitory concentration [IC50] = 0.61 μM; dissociation constant [Kd] = 1.3 μM). These quantitative parameters demonstrate the potent biochemical inhibitory activity of USP21-in6 toward USP21, supporting its suitability for subsequent cellular and in-vivo functional studies. This compound suppresses NSCLC proliferation and induces apoptosis, while exhibiting low toxicity toward normal cells. Mechanistically, USP21 stabilized stearoyl-CoA desaturase 1 (SCD1); USP21-in6 disrupted this USP21-SCD1 axis, triggering SCD1 degradation and blocking fatty acid synthesis. USP21-in6 monotherapy showed robust anti-tumor activity and boosted anti-programmed cell death protein 1 (PD-1) therapy by remodeling the tumor immune microenvironment: it enhanced cluster of differentiation 8-positive (CD8+) T-cell function and destabilized forkhead box protein 3 (Foxp3) to suppress regulatory T cells (Tregs). It lowered SCD1-derived monounsaturated fatty acids (C16:1, C18:1) in tumors and serum. Clinically, co-upregulated USP21 and SCD1 correlated with PD-1 inhibitor resistance. Conclusion: This work identifies USP21 as an important immunometabolic regulator in NSCLC. Targeting USP21 with USP21-in6 supports further investigation of USP21 inhibition as a potential dual strategy to overcome metabolic disorders and immune suppression for NSCLC immunometabolic therapy.
SN - 0965-0407
SN - 1555-3906
ER -