bims-cutpro 2026-02-08 papers

bims-cutpro

Biomed News

on Cullin targeted protein degradation

Issue of 2026–02–08
twenty-one papers selected by
James M. Krieger, Francis Crick Institute

Mezigdomide combined with bortezomib disrupts the cell cycle and elicits superior antitumor effects in multiple myeloma.
Targeting Ikaros and Aiolos: Next-Generation Cereblon E3 Ligase Modulators in MM.
Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma.
YAP Inhibits HIV-1 transcription and promotes HIV-1 latency by regulating E3 ubiquitin ligase UHRF1 mediated tat degradation.
Emerging Biologic Modalities for Targeted Protein Degradation.
Cis or trans: a puzzle of Parkin activation mechanism.
TRIM21enhances IL-17A signaling and drives autoimmune myocarditis by promoting TRAF3 lysosomaldegradation in cardiac fibroblasts.
Direct receptor competition gates RGL2 proteolysis for seed germination timing in Arabidopsis.
RNF6 activates JNK/c-JUN pathway in ovarian cancer by promoting K48-linked NME4 ubiquitination.
Ubiquitination-Mediated Degradation of SlVPS29 by the SlHSFA7-SlRNF185 Module Enhances Tomato Pollen Thermotolerance.
The ubiquitination-autophagy axis in cancer therapy resistance: mechanistic insights and therapeutic opportunities.
Ubiquitin regulatory code: unraveling tumor cell ferroptosis.
E3 ubiquitin ligase Peli1 promotes ferroptosis in granulosa cells in PCOS by degrading Fth1.
Proanthocyanidins enhance antitumor immunity by promoting ubiquitin-proteasomal PD-L1 degradation via stabilization of LKB1 and SYVN1.
Protein C-terminal variations impact proteostasis.
Proteome-wide C-degron activity profiling connects conditional regulation of the CTLH E3 ligase complex to ribosome biogenesis.
Ufd2p promotes efficient crossover formation by destabilizing Top2p during meiosis.
Fenofibrate potentiates the therapeutic efficacy of EZH2 inhibitors on melanoma via TRIM21- and OTUD4-mediated EZH2 ubiquitination.
Synergistic targeting of the ARID2-MYC axis by pomalidomide and panobinostat overcomes intrinsic IMiD resistance in multiple myeloma.
KLHL20 alleviates high glucose-induced mitochondrial apoptosis in renal tubular cells by targeting DAPK1 for ubiquitination and degradation.
Interstitial cystitis-related gene CCDC8 accelerates tumorigenesis by participating in CUL7-mediated degradation of P53 in bladder cancer.

Blood Neoplasia. 2026 Feb;3(1): 100179

Mezigdomide combined with bortezomib disrupts the cell cycle and elicits superior antitumor effects in multiple myeloma.

Chad C Bjorklund, Marta Larrayoz, Jian Kang, Hsiling Chiu, Natasha Shtraizent, Lei Wu, Shirong Li, Chih-Chao Hsu, Junfei Zhao, Michael Amatangelo, Tracy T Chow, Krista Wollerman, Ram Kumar Singh, Sneha Sridhara, Shailesh Dudhgaonkar, Prakash Subramanyam, Kaushik Ghosh, Paul G Richardson, Nizar J Bahlis, Anjan Thakurta, Jose A Martinez-Climent, Anita K Gandhi, Patrick R Hagner.

Triplet regimens that include an immunomodulatory agent, proteasome inhibitor, and dexamethasone are widely used in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM). Mezigdomide (MEZI; CC-92480) is a cereblon E3 ubiquitin ligase modulator that is being clinically investigated in combination with bortezomib (BTZ) and low-dose dexamethasone (DEX) for safety and efficacy in pretreated R/RMM. The single-agent mechanism of action (MOA) of MEZI has been defined by the recruitment and degradation of essential MM transcription factors Ikaros and Aiolos, leading to cell autonomous antitumor effects and immune modulation. These effects were confirmed in patients based on pharmacodynamic measurements of Ikaros/Aiolos degradation in biomarker evaluations of immune subsets. However, the MOA of triplet regimens, including that of MEZI/BTZ/DEX remain poorly defined. To better understand the MOA of this triplet combination, we compared the mechanistic contributions of MEZI, BTZ, or DEX alone, or in combination, in preclinical MM models in vitro and in vivo. Additionally, we have compared these results with similar combinations with the immunomodulatory agent pomalidomide (POM). Our studies indicate that the MEZI/BTZ/DEX triplet is superior to all single agents and POM/BTZ/DEX in terms of potency of antiproliferative and proapoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show that the combination of MEZI with BTZ increases cell death through disruption of multiple phases of the cell cycle and this thereby enhances the direct cytotoxic effects of the combination treatment.

DOI: https://doi.org/10.1016/j.bneo.2025.100179
Eur J Haematol. 2026 Feb 06.

Targeting Ikaros and Aiolos: Next-Generation Cereblon E3 Ligase Modulators in MM.

Maria Eugenia Alvaro, Enrica Antonia Martino, Santino Caserta, Mamdouh Skafi, Antonella Bruzzese, Nicola Amodio, Eugenio Lucia, Virginia Olivito, Caterina Labanca, Francesco Mendicino, Ernesto Vigna, Fortunato Morabito, Massimo Gentile.

  Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by recurrent relapses and eventual refractoriness to standard agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies. With frontline therapeutic strategies increasingly employing quadruplet induction regimens and prolonged lenalidomide maintenance, resistance to traditional IMiDs has become more prevalent, creating an urgent need for next-generation cereblon E3 ligase modulators (CELMoDs) capable of overcoming IMiD refractoriness and enhancing the immunologic microenvironment. Iberdomide (CC-220) and mezigdomide (CC-92480) are rationally engineered CELMoDs designed to achieve deeper degradation of Ikaros (IKZF1) and Aiolos (IKZF3), restore cereblon-mediated activity, and potentiate immune effector responses. This review explores the core biological features of these agents, detailing their mechanisms of action, preclinical and clinical activity, as well as safety profile. We examine how their pharmacodynamic properties differ from classical IMiDs, their relevance in triple-class and penta-refractory MM, and their integration into emerging combination strategies with monoclonal antibodies and T-cell-redirecting immunotherapies. Special emphasis is placed on ongoing and future trials that may refine their therapeutic positioning, alongside a critical appraisal of the limitations and future directions of this rapidly advancing drug class.

Keywords:  Cereblon E3 ligase modulators (CELMoDs); IMiD resistance/immunomodulation; Iberdomide; Mezigdomide; multiple myeloma

DOI:  https://doi.org/10.1111/ejh.70134
Cell Death Discov. 2026 Jan 30. 12(1): 88

Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma.

Guangyi Wang, Yibang Shen, Lin Wang, Tao Fu, Yichuan Huang, Fangyu Chai, Mingjin Xu, Yan Jiang, Jisheng Zhang.

Hypopharyngeal squamous cell carcinoma (HPSCC) is a highly aggressive malignancy with a poor prognosis. This study elucidates the role of the E3 ubiquitin ligase Tripartite Motif Containing 15 (Trim15) and its substrate, mitochondrial voltage-dependent anion channel 3 (VDAC3), in regulating autophagy, mitophagy, and chemoresistance in HPSCC. We found that Trim15 is significantly downregulated in HPSCC tissues and inhibits cell proliferation and migration in FaDu and Detroit 562 cells. Trim15 stabilizes VDAC3 via K6-linked ubiquitination, thereby suppressing autophagy and mitophagy while elevating reactive oxygen species (ROS) levels. VDAC3 knockdown enhances autophagy and mitophagy, concomitantly reducing ROS and promoting cancer cell survival. High-concentration ethanol suppresses Trim15 and VDAC3 expression, suggesting an adaptive response to oxidative stress. Notably, chloroquine (CQ), an autophagy inhibitor, enhances HPSCC sensitivity to 5-fluorouracil (5-FU), with synergistic effects observed in xenograft models. These findings establish the Trim15-VDAC3-mitophagy axis as a critical regulator of HPSCC progression and chemoresistance, offering a novel therapeutic target for augmenting the efficacy of autophagy inhibitors in combination with standard chemotherapy.

DOI: https://doi.org/10.1038/s41420-026-02943-0
PLoS Pathog. 2026 Jan;22(1): e1013906

YAP Inhibits HIV-1 transcription and promotes HIV-1 latency by regulating E3 ubiquitin ligase UHRF1 mediated tat degradation.

Chenliang Zhou, Hong He, Yuzai Zhang, Xiaolian Liu, Muye Xia, Jiayin Qiu, Ziyao Wu, Huba Khamis Rashid, Wenli Liu, Jie Peng, Lin Li.

The latency of human immunodeficiency virus type 1 (HIV-1) is a major barrier to achieving an HIV-1 cure, as antiretroviral therapy does not target the latent virus. Virus-host interactions play an essential role in various stages of the HIV-1 lifecycle. Exploring the interaction between host factors and HIV-1 infection is critical for developing new HIV-1 treatment strategies. Yes-associated protein (YAP) is a key co-transcription factor in the Hippo signaling pathway, which regulates the occurrence and development of various diseases, including cellular metabolism, cancer, immunity, and viral infection. In this study, we first confirmed that YAP gene expression in patients with acquired immune deficiency syndrome (AIDS) was significantly lower than that in the healthy control group, as determined using the GEO2R online tool. Furthermore, YAP was identified as a negative regulator of HIV-1 transcription by mediating K33- and K48-linked ubiquitination and proteasomal degradation of Tat. Here, we further confirmed that the YAP TAD domain recruited ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to mediate Tat's ubiquitination and degradation by the screening of the BioGRID database combined with IP-MS analysis. The conserved lysine residues K28, K29, and K41 on Tat were critical acceptor sites for ubiquitination and proteasomal degradation. Our findings revealed that YAP promotes the suppression of HIV-1 transcription and the maintenance of HIV-1 latency, providing novel insights into virus-host interactions for regulating HIV-1 latency.

DOI: https://doi.org/10.1371/journal.ppat.1013906
J Biol Chem. 2026 Feb 04. pii: S0021-9258(26)00118-3. [Epub ahead of print] 111248

Emerging Biologic Modalities for Targeted Protein Degradation.

Alana G Caldwell, Harshil Parmar, Xiaoyu Zhang.

Targeted protein degradation (TPD) has emerged as a powerful approach for eliminating disease-associated proteins by harnessing the ubiquitin-proteasome system. Biologic degraders are modular protein chimeras that recruit ubiquitin machinery to target proteins. They offer high specificity, modular design, and the ability to access targets traditionally considered challenging for small molecule ligands. This review surveys the expanding landscape of biologic TPD modalities, highlighting E3 ligase- and E2 enzyme-based degraders, TRIM-Away and TRIMbody-Away systems, and diverse biologics-based ligands that serve as target-binding components. We also discuss emerging peptide-based strategies, which bridge biologic and synthetic approaches. Finally, we highlight future opportunities to improve biologic degraders and their potential to expand the scope of targeted protein degradation.

DOI: https://doi.org/10.1016/j.jbc.2026.111248
Essays Biochem. 2026 Feb 02. pii: EBC20253048. [Epub ahead of print]69(5):

Cis or trans: a puzzle of Parkin activation mechanism.

Mohini Sherawat, Ankit Kumar, Dipti Ranjan Lenka, Atul Kumar.

  The PARK2 gene, which encodes the E3 ubiquitin ligase Parkin, and the PARK6 gene, encoding phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), are frequently mutated in patients with Parkinson's disease (PD). Parkin is normally maintained in an autoinhibited conformation, and its activation is triggered by PINK1-mediated phosphorylation of both ubiquitin or NEDD8 and Parkin's ubiquitin-like (Ubl) domain. This review provides a comprehensive overview of the models proposed over the past decade to explain Parkin's autoinhibition and activation. We summarize key structural and biophysical studies that have progressively uncovered the molecular basis of Parkin activation, tracing the evolution of these insights. This review concludes by discussing the intriguing and still unresolved question of whether Parkin activation occurs through a cis or trans mechanism and outlines future directions for research aimed at understanding these pathways.

Keywords:  PINK1; Parkin; Parkinson’s; mitophagy; ubiquitin

DOI:  https://doi.org/10.1042/EBC20253048
Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2426265123

TRIM21enhances IL-17A signaling and drives autoimmune myocarditis by promoting TRAF3 lysosomaldegradation in cardiac fibroblasts.

Yahui Song, Xuege Huang, Lin Wei, Wenwen Shen, Jiapeng Gao, Kai Hou, Bin Yang, Yi Wang, Guang Hu, Wei Xu, Jing Guo, Wenlong Lin, Min Li.

  Myocarditis is a potentially fatal disease that can progress to inflammatory dilated cardiomyopathy (DCMi), a condition that is a leading cause of noncongenital heart failure in young adults. However, the mechanisms driving the transition from acute myocarditis to DCMi remain poorly understood. Although IL-17A-mediated inflammation is a well-known driver of this progression, the intracellular regulators that sustain and amplify this response remain unclear. Here, we identify the E3 ubiquitin ligase TRIM21, which is upregulated in the hearts of DCMi patients and experimental autoimmune myocarditis (EAM) mice, as a key amplifier of IL-17A-driven inflammation in cardiac fibroblasts (CFs), promoting disease progression and fibrosis. TRIM21 deficiency significantly attenuates EAM progression, reducing inflammatory cell infiltration and fibrotic remodeling. Mechanistically, TRIM21 is induced by IL-17A in CFs and promotes K27-linked polyubiquitination and lysosomal degradation of TRAF3, a negative regulator of IL-17A signaling, thereby establishing a self-reinforcing IL-17A-TRIM21-TRAF3 positive feedback loop. Finally, specific knockdown of TRIM21 in CFs via the AAV9-Postn strategy effectively alleviates EAM severity. These findings identify TRIM21 as an intracellular mediator of sustained IL-17A signaling in myocarditis and highlight its potential as a therapeutic target for preventing progression to DCMi.

Keywords:  IL-17A; TRAF3; TRIM21; autoimmune myocarditis; cardiac fibroblasts

DOI:  https://doi.org/10.1073/pnas.2426265123
EMBO J. 2026 Feb 02.

Direct receptor competition gates RGL2 proteolysis for seed germination timing in Arabidopsis.

Kaili Nie, Juntao Jiang, Changgen Xie, Hongyun Zhao, Yuan Zheng.

  Seed germination is orchestrated by antagonistic gibberellin (GA) and abscisic acid (ABA) signals converging on the master germination repressor RGL2. Here, we unveil a receptor-competition paradigm where ABA receptors (PYLs) stabilize RGL2, both through direct physical interaction and through functional sequestration of DWA1, the CUL4-DDB1 E3 ligase substrate adapter mediating RGL2 ubiquitination. GA receptors (GID1s) counteract this stabilization by competitively displacing PYLs from RGL2, leveraging their superior binding capacity to license DWA1-mediated degradation. Crucially, this competition is defined by the concentration of abscisic acid and gibberellin as they regulate PYL and GID1 expression. Genetic epistasis confirms that PYLs act upstream of DWA1, competing directly with GID1 at RGL2. This receptor-occupied switch converts environmental fluctuations into proteolytic decisions: transient stress imposes a reversible "pause state" through PYL dominance, while sustained GA biosynthesis permits germination via GID1-mediated degradation. Our work establishes direct receptor competition as a complementary layer to hormone crosstalk, providing a universal framework for signal-driven developmental transitions.

Keywords:  Hormone Crosstalk; Proteolytic Switch; Receptor Competition; Seed Germination Timing

DOI:  https://doi.org/10.1038/s44318-026-00704-4
Pathol Res Pract. 2026 Mar;pii: S0344-0338(26)00017-8. [Epub ahead of print]279 156366

RNF6 activates JNK/c-JUN pathway in ovarian cancer by promoting K48-linked NME4 ubiquitination.

Taoqiong Li, Fei Qian, Yumei Chen, Wei Li.

   BACKGROUND: RING finger protein 6 (RNF6), a member of the E3 ubiquitin ligase family, has been implicated in various cancers, yet its functional significance and regulatory mechanisms in ovarian cancer (OC) are poorly understood.
METHODS: RNF6 expression levels were analyzed using TCGA data and confirmed by IHC, qRT-PCR, and western blotting in OC tissues or cell lines. Functional roles of RNF6 were evaluated through CCK-8, colony formation, wound healing, Transwell, and EMT marker assays. Protein interactions and ubiquitination patterns were investigated via Co-IP, CHX chase, and ubiquitination assays. Rescue experiments were conducted by co-modulating RNF6 and NME4 expression. In vivo tumorigenesis was assessed using a nude mouse xenograft model.
RESULTS: RNF6 was markedly overexpressed in OC and associated with poor prognosis. Silencing RNF6 suppressed cell growth, invasive behavior, and EMT, while enhancing NME4 expression. Mechanistic analyses demonstrated that RNF6 directly binds to NME4 and facilitates its K48-linked polyubiquitination, leading to proteasomal degradation. Knockdown of NME4 reversed the tumor-suppressive effects of RNF6 depletion and reinstated JNK/c-JUN pathway activation. In vivo, RNF6 silencing significantly reduced tumor burden and impaired downstream signaling events.
CONCLUSION: RNF6 contributed to OC malignancy by destabilizing NME4 and activating the JNK cascade. This newly identified RNF6/NME4/JNK axis provides potential targets for therapeutic intervention in OC.

Keywords:  EMT; JNK signaling; NME4; Ovarian cancer; RNF6; Tumor progression; Ubiquitination

DOI:  https://doi.org/10.1016/j.prp.2026.156366
Plant Biotechnol J. 2026 Feb 06.

Ubiquitination-Mediated Degradation of SlVPS29 by the SlHSFA7-SlRNF185 Module Enhances Tomato Pollen Thermotolerance.

Xiaolin Geng, Qinqin Yang, Hongwei Li, Xunwen Peng, Wenbo Zhang, Huihui Wang, Yushan Li, Fang Li, Quanquan Chen, Tao Lin.

  High temperature has posed significant challenges to global agriculture, markedly leading to reduced fertility and yield losses in tomato (Solanum lycopersicum). Therefore, thermotolerance-conferring genes and loci are needed to further improve cultivated tomatoes. Here we identified an E3 ubiquitin ligase SlRNF185, containing a C3HC4-type RING-HC domain, that confers tomato pollen thermotolerance. As a predominant ubiquitination member, SlRNF185 could degrade the SlVPS29 protein induced by heat stress to enhance thermotolerance. Mechanistically, we found that a heat shock transcription factor SlHSFA7 dramatically activates the expression of SlRNF185 under heat stress and acts as a positive regulator of tomato pollen thermotolerance. Collectively, our findings reveal that a SlHSFA7-SlRNF185 genetic module regulates ubiquitination-mediated degradation of SlVPS29 under heat stress, providing the strategy for breeding thermotolerance tomato varieties.

Keywords:  pollen; thermotolerance; tomato; ubiquitination

DOI:  https://doi.org/10.1111/pbi.70583
Front Pharmacol. 2025 ;16 1722559

The ubiquitination-autophagy axis in cancer therapy resistance: mechanistic insights and therapeutic opportunities.

Hengrui Zhang, Hanxi Yan, Yulin Liu, Anqi Zeng, Linjiang Song.

  Therapy resistance is a major challenge in cancer treatment. Growing evidences reveal that the interaction between ubiquitination and autophagy plays a key role in regulating resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. In this review, we systematically summarize recent studies that reveal how specific E3 ligases, deubiquitinating enzymes, and ubiquitin-like modifiers influence autophagic flux and modulate the tumor response. We focus on key regulatory circuits-such as the Tripartite-motif protein 65-miR-138-5p-Autophagy related 7 (TRIM65-miR-138-5p-ATG7)pathway in non-small cell lung cancer, the Cullin-RING Ligase 4(CRL4)-mitophagy signaling pathway in ovarian cancer, and the Ubiquitin Specific Peptidase 14-S-phase kinase-associated protein 2(USP14-Skp2) axis in B-Raf proto-oncogene (BRAF) inhibitor resistance-illustrating the dual regulatory functions of ubiquitin-dependent protein turnover and autophagy. Furthermore, we highlight how noncoding RNAs and the tumor microenvironment influence ubiquitination-modulated autophagy and contribute to immune resistance or DNA repair remodeling. Finally, we discuss potential therapeutic strategies, including Proteolysis Targeting Chimeras (PROTACs), dual E3 ligase/autophagy inhibitors, and autophagy flux modulators, to overcome resistance and enhance treatment efficacy across multiple cancer types. These insights establish the foundation for targeting the ubiquitin-autophagy network as a cohesive strategy to combat refractory cancer.

Keywords:  E3 ligase; autophagy; chemotherapy; immune therapy; radiotherapy; targeted therapy; therapy resistance; ubiquitination

DOI:  https://doi.org/10.3389/fphar.2025.1722559
Crit Rev Oncol Hematol. 2026 Feb 04. pii: S1040-8428(26)00059-4. [Epub ahead of print] 105172

Ubiquitin regulatory code: unraveling tumor cell ferroptosis.

Xinjing Liu, Jian Liu, Wenqing Chen, Jimei Zhang, Yiju Wei, Lili Sun.

  Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, characterized by the inhibition of glutathione peroxidase 4 (GPX4), glutathione (GSH) depletion, and peroxidation of polyunsaturated fatty acids (PUFAs). Due to metabolic reprogramming and impaired antioxidant defenses, tumor cells exhibit heightened sensitivity to ferroptosis, positioning it as a promising therapeutic target for cancer. Within the cellular protein regulatory network, post-translational modifications (PTMs) -particularly ubiquitination and ubiquitin-like modifications (Ubls, including SUMOylation, NEDDylation, UFMylation, and ATG8ylation) -serve as molecular switches by modulating the stability of key proteins such as GPX4 and SLC7A11. This review systematically dissects how E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) orchestrate redox homeostasis and iron metabolism, through site-specific ubiquitination of critical proteins. Furthermore, we highlight the development of small-molecule inhibitors targeting these modifications, emphasizing their potential to disrupt ferroptosis resistance pathways. By integrating mechanistic insights with therapeutic applications, this study not only elucidates the dynamic complexity of ubiquitin-mediated regulatory networks but also proposes innovative strategies leveraging Ub/Ubl modifications for targeted cancer therapy. These findings provide a foundational theoretical framework and actionable research directions for advancing precision medicine in oncology.

Keywords:  Ferroptosis; tumor; ubiquitin-like modifications; ubiquitination

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105172
J Steroid Biochem Mol Biol. 2026 Jan 29. pii: S0960-0760(26)00014-2. [Epub ahead of print] 106948

E3 ubiquitin ligase Peli1 promotes ferroptosis in granulosa cells in PCOS by degrading Fth1.

Xiaomeng Zha, Liang Chen, Zhaoping Tan, Tiancheng Wu, Qiaohua Xiong, Haihua Wang, Yuanyuan Kuang, Fei Xing, Aihua Lu, Lili Sun, Yuanzhen Zhang.

  Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age, characterized by hyperandrogenemia and obstruction of ovulation. However, the underlying mechanisms of ovarian abnormalities in PCOS remain to be investigated. In this study, we first identified altered levels of ovarian ferroptosis in the PCOS population by screening a web-based database. Further, we established a prasterone-exposed PCOS mouse model and a granulosa cell model to confirm that hyperandrogenism can lead to the development of ferroptosis in ovarian granulosa cells. The transcriptome sequencing and cellular experiments were conducted to explore the possible mechanisms. It was found that the ubiquitination pathway and P53 pathway are significantly enriched in the prasterone-exposed granulosa cells. The E3 ubiquitin ligase PELI1 gene is significantly highly expressed in PCOS ovaries and may contribute to ferroptosis by degrading FTH1. In addition, high expression of the P53 gene was associated with alterations in PELI1/FTH1. This study confirmed that hyperandrogenism can mediate the development of ovarian ferroptosis via the P53/PELI1/FTH1 pathway and the E3 ubiquitin ligase PELI1 plays an important regulatory role. In vivo, the iron death inhibitor deferoxamine mesylate could alleviate ferroptosis and follicular development disorder in the ovaries of PCOS mice. This study provides new insights into the pathological changes of PCOS ovaries and possible interventions for the treatment of PCOS.

Keywords:  ferroptosis; polycystic ovary syndrome; ubiquitination

DOI:  https://doi.org/10.1016/j.jsbmb.2026.106948
J Clin Invest. 2026 Feb 02. pii: e197592. [Epub ahead of print]136(3):

Proanthocyanidins enhance antitumor immunity by promoting ubiquitin-proteasomal PD-L1 degradation via stabilization of LKB1 and SYVN1.

Mengting Xu, Xuwen Lin, Hanchi Xu, Hongmei Hu, Xinying Xue, Qing Zhang, Dianping Yu, Saisai Tian, Mei Xie, Linyang Li, Xiaoyu Tao, Xinru Li, Simeng Li, Shize Xie, Yating Tian, Xia Liu, Hanchen Xu, Qun Wang, Weidong Zhang, Sanhong Liu.

  Programmed cell death 1 ligand 1-targeted (PD-L1-targeted) immune checkpoint inhibitors are revolutionizing cancer therapy. However, strategies to induce endogenous PD-L1 degradation represent an emerging therapeutic paradigm. Here, we identified proanthocyanidins (PC) as a potent inducer of PD-L1 degradation through an endoplasmic reticulum-associated degradation (ERAD) mechanism. Mechanistically, PC exerted dual effects: First, it targeted and stabilized LKB1 to activate AMPK in tumor cells, subsequently inducing the phosphorylation of PD-L1 at Ser195 - a disruption that in turn impaired glycosylation of PD-L1 and promoted its retention in the ER. Second, PC directly bound to the E3 ubiquitin ligase SYVN1 to increase its protein stability, which strengthened PD-L1-SYVN1 binding, thereby accelerating K48-linked ubiquitination and proteasomal degradation of ER-retained PD-L1. This cascade culminated in the activation of CD8+ T cell-dominated antitumor immune responses, accompanied by suppression of myeloid-derived suppressor cells and regulatory T cells. In preclinical models of lung and colorectal cancer, PC exhibited synergistic antitumor efficacy when combined with anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) antibodies. Notably, PC also potently inhibited the progression of azoxymethane/dextran sodium sulfate-induced orthotopic colorectal cancer in mice. Collectively, our findings unveil an antitumor mechanism of PC, establishing this small-molecule compound as an ERAD pathway-exploiting immune checkpoint modulator with promising translational potential for cancer therapy.

Keywords:  Cancer immunotherapy; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI197592
Nat Commun. 2026 Feb 03.

Protein C-terminal variations impact proteostasis.

Ching-Yu Chu, Shu-Yu Hsu, Chi-Wei Yeh, Kun-Hai Yeh, Li-Chin Wang, Lo-Tung Lee, Shu-Chuan Chen, Chen-Hsin Yu, Hsueh-Chi S Yen.

Protein C-termini can vary due to errors or programmed regulation, contributing to proteome diversity, yet their impact on the proteome remains poorly understood. Although aberrant C-termini are often linked to protein degradation, it is unclear if this holds true universally. In this study, we examine how C-terminal variations-arising from disease-associated nonstop mutations, alternative splicing, and translational readthrough-affect protein half-lives. Our findings indicate that, contrary to previous studies, erroneous C-termini can either stabilize or destabilize proteins. We have identified multiple oncoproteins and tumor suppressors whose protein stability is altered by disease-relevant nonstop mutations. Notably, we have found that C-terminal variations commonly influence the stability of canonical proteins, extending beyond their role in protein quality control. Furthermore, we have uncovered C-terminal features that distinguish erroneous from wild-type proteins and reveal that hydrophobic C-termini are targeted by a complex ubiquitin ligase network. Overall, our work broadens the understanding of C-terminal-dependent protein degradation and supports that C-terminal variation is a widespread strategy for generating protein forms with distinct half-lives to exert diverse biological functions.

DOI: https://doi.org/10.1038/s41467-026-68979-z
bioRxiv. 2026 Jan 14. pii: 2026.01.14.698769. [Epub ahead of print]

Proteome-wide C-degron activity profiling connects conditional regulation of the CTLH E3 ligase complex to ribosome biogenesis.

Drew W Grant, Shengjiang Tan, Dylan E Ramage, Mamie Z Li, Ying Di, Iva A Tchasovnikarova, Michael P Weekes, Stephen J Elledge, Alan J Warren, Richard T Timms.

Many E3 ubiquitin ligases recognize cognate degron motifs located at protein termini, but the paucity of bona fide substrates of N-degron and C-degron pathways hampers our understanding of their physiological significance. Here, by devising an expression screening approach to assess the effect of C-terminal "capping" on the stability of thousands of human proteins, we systematically identify a suite of full-length substrates harboring C-terminal degrons. Interrogating one leading candidate, ZMYND19, we characterize a C-degron pathway governed by the Muskelin substrate adaptor of the CTLH E3 ligase complex. Cell-to-cell variability in ZMYND19 stability uncovered conditional regulation, with CTLH-mediated degradation impaired by TNF-α stimulation but enhanced by mTOR inhibition. Parallel genetic and proteomic screens identified two poorly characterized proteins, AAMP and AEN, as additional substrates of the CTLH Muskelin C-degron pathway, leading us to define an essential role for AAMP in ribosome maturation through chaperone activity towards ribosomal protein uL16. Altogether, these data define a C-degron pathway through which the Muskelin substrate adaptor connects conditional regulation of the CTLH E3 ligase complex to control of ribosome biogenesis.

DOI: https://doi.org/10.64898/2026.01.14.698769
Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2517398123

Ufd2p promotes efficient crossover formation by destabilizing Top2p during meiosis.

Taicong Tan, Yanan Zhao, Yinghong Chen, Yali Mi, Jiaxin Zeng, Peng Du, Tingting Han, Yawen Liu, Ning Li, Jun Kong, Liying Wang, Yang Yu, Mulin Jun Li, Liangran Zhang, Wei Li, Chao Liu.

  Proper crossover (CO) formation in meiosis serves dual roles in ensuring accurate chromosome segregation and generating genetic diversity. However, the molecular mechanisms underlying CO number and distribution remain incompletely understood. Previous studies have implicated the ubiquitin-proteasome system in CO regulation, but specific regulators and mechanisms are poorly defined. Here, we identify the E3 ubiquitin ligase Ufd2p as a key regulator promoting efficient CO formation through a focused genetic screen in Saccharomyces cerevisiae. Deletion of UFD2 significantly reduces CO frequency by enhancing the strength of CO interference. Integrated multiomics analysis indicates that Ufd2p targets Topoisomerase II (Top2p) for ubiquitination and subsequent proteasomal degradation during meiosis. Deletion of UFD2 results in Top2p accumulation, which resolves DNA negative supercoils excessively and enhances CO interference in the nucleus, ultimately reducing CO numbers. We further show that the mammalian homolog of Ufd2p, UBE4B, plays a conserved role in promoting efficient CO formation by regulating TOP2A-dependent DNA negative supercoils dynamics. Notably, expression of mouse or human UBE4B in yeast restores CO formation and meiotic progression in UFD2 deletion cells, demonstrating functional conservation across species. Together, our work identifies Ufd2p as a previously uncharacterized regulator of CO formation and provides important insights into the conserved molecular mechanism, which operates through Top2p-mediated supercoils homeostasis.

Keywords:  Top2p; Ufd2p; crossover interference; meiotic recombination; ubiquitin ligase

DOI:  https://doi.org/10.1073/pnas.2517398123
Br J Pharmacol. 2026 Feb 07.

Fenofibrate potentiates the therapeutic efficacy of EZH2 inhibitors on melanoma via TRIM21- and OTUD4-mediated EZH2 ubiquitination.

Rui Cheng, Yuanjun Tang, Xuedi Cao, Xiaotong Yu, Zhanya Huang, Yunyun Guo, Renjing Jin, Yan Wang, Yang Liu, Lixiang Xue, Yuqing Wang.

   BACKGROUND AND PURPOSE: EZH2 (enhancer of zeste homologue 2) inhibitors are an emerging class of drugs that target epigenetic regulation. However, their efficacy in solid tumours has been limited, partly due to drug-induced upregulation of fatty acid synthesis. Combining lipid metabolic modulation with EZH2 inhibition may offer a promising strategy to enhance antitumor activity.
EXPERIMENTAL APPROACH: We conducted a screen of clinically approved lipid-lowering drugs to identify candidates that could enhance the efficacy of EZH2 inhibitors and found that fenofibrate significantly potentiated the antitumor effects of EZH2 inhibition. Mechanistic studies revealed that this synergistic effect was associated with the degradation of EZH2 protein. To uncover the underlying regulatory pathway, we performed mass spectrometry analysis, which identified the E3 ubiquitin ligase TRIM21 and the deubiquitinase OTUD4 as key mediators of fenofibrate-induced EZH2 degradation.
KEY RESULTS: Fenofibrate significantly enhanced the antitumor effects of EZH2 inhibitors in melanoma, independent of its conventional lipid-lowering function. TRIM21 and OTUD4 were identified as critical mediators of this synergistic effect. Fenofibrate disrupted the non-canonical functions of EZH2 by promoting its destabilization, thereby exerting dual effects-inhibiting EZH2 enzymatic activity and accelerating its degradation. Combination therapy with fenofibrate and EZH2 inhibitors resulted in a potent synergistic suppression of tumour growth.
CONCLUSIONS AND IMPLICATIONS: Our findings reveal a previously unrecognized role for fenofibrate in augmenting EZH2-targeted therapy. This study provides a novel strategy to improve the efficacy of epigenetic therapies in cancer by combining EZH2 inhibitors with fenofibrate, offering potential clinical benefits for precision oncology.

Keywords:  EZH2; OTUD4; TRIM21; fenofibrate; melanoma; targeted therapy; ubiquitination

DOI:  https://doi.org/10.1111/bph.70357
Sci Rep. 2026 Feb 05.

Synergistic targeting of the ARID2-MYC axis by pomalidomide and panobinostat overcomes intrinsic IMiD resistance in multiple myeloma.

Junichi Yamamoto, Tomoko Asatsuma-Okumura, Takumi Ito, Yoshiko Iwai, Hiroshi Handa, Yuki Yamaguchi.

Multiple myeloma remains a therapeutic challenge despite recent advances with proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Among new approaches, the combination of IMiDs and histone deacetylase inhibitors has shown promise in relapsed or refractory multiple myeloma. Here, we elucidate the molecular basis of their synergy and its role in overcoming drug resistance in myeloma cells. We demonstrate that these agents converge to downregulate the master oncogene MYC, resulting in synergistic cytotoxicity. Importantly, this effect persists even in models intrinsically resistant to IMiDs, where the canonical IKZF1/3-IRF4/MYC axis is functionally uncoupled. In this context, the combination engages an alternative ARID2-MYC axis, mediated by the synergistic downregulation of the IMiD neosubstrate ARID2. This finding highlights the functional relevance of IMiD's inherent polypharmacology in circumventing primary resistance mechanisms at the cellular level. Together, our results identify the ARID2-containing PBAF complex as a critical vulnerability in resistant myeloma cells and provide a mechanistic rationale for designing combination strategies that co-target this complex, with the potential to enhance therapeutic efficacy by overcoming drug resistance.

DOI: https://doi.org/10.1038/s41598-026-37740-3
Biochem Biophys Res Commun. 2026 Jan 25. pii: S0006-291X(26)00109-9. [Epub ahead of print]805 153345

KLHL20 alleviates high glucose-induced mitochondrial apoptosis in renal tubular cells by targeting DAPK1 for ubiquitination and degradation.

Yi Lei, Chenlin Gao, Xin Zhao, Betty Yuen Kwan Law, Yong Xu.

  Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, driven by hyperglycemia-induced mitochondrial apoptosis in renal tubular epithelial cells. Death-associated protein kinase 1 (DAPK1) is a key mediator of cell death, but its regulation in DKD remains unclear. Here, we investigated the mechanisms underlying DAPK1 upregulation and its role in mitochondrial apoptosis under high glucose (HG) conditions in HK-2 cells and db/db mouse models. In db/db mice, renal DAPK1 protein levels were elevated, while KLHL20 levels were reduced, correlating with glomerular and tubular injury. In HK-2 cells, HG (33 mM, 48 h) significantly increased DAPK1 mRNA and protein levels while prolonging its half-life. Mechanistically, HG transcriptionally suppressed KLHL20, an E3 ubiquitin ligase adaptor that targets DAPK1 for proteasomal degradation. Co-immunoprecipitation confirmed KLHL20-DAPK1 interaction and showed reduced DAPK1 ubiquitination under HG. Overexpression of KLHL20 restored DAPK1 ubiquitination and reduced its protein levels without affecting mRNA, confirming post-translational regulation. Functionally, DAPK1 knockdown attenuated HG-induced mitochondrial apoptosis. KLHL20 overexpression similarly protected against HG-induced apoptosis, but this effect was abrogated by DAPK1 co-overexpression, establishing DAPK1 as a critical downstream effector. These findings reveal a novel KLHL20-DAPK1 axis where HG stabilizes DAPK1 by downregulating KLHL20, promoting mitochondrial apoptosis in renal tubular cells. Targeting this pathway may offer therapeutic strategies for DKD.

Keywords:  DAPK1; Diabetic kidney disease; KLHL20; Mitochondrial apoptosis

DOI:  https://doi.org/10.1016/j.bbrc.2026.153345
Oncogene. 2026 Feb 05.

Interstitial cystitis-related gene CCDC8 accelerates tumorigenesis by participating in CUL7-mediated degradation of P53 in bladder cancer.

Jiawen Wang, Jinfu Wang, Lingfeng Meng, Xinhao Wang, Zehao Yan, Honghong Pan, Jiayue Wu, Qidong Zhou, Liefu Ye, Jinfeng Wu, Yaoguang Zhang, Jianye Wang.

Bladder cancer remains a clinically challenging malignancy, with increasing evidence suggesting that chronic bladder inflammation, such as interstitial cystitis (IC), may contribute to its development. However, the molecular mechanisms linking inflammation to tumorigenesis are poorly understood. Here, we identify coiled-coil domain-containing 8 (CCDC8) as a potential oncogenic factor in bladder cancer. Transcriptomic analysis revealed that CCDC8 is dysregulated in both IC and bladder cancer, with overexpression confirmed in tumor tissues and cell lines. Elevated CCDC8 expression was significantly associated with advanced tumor stage, lymph node metastasis, and poor prognosis, particularly in patients harboring wild-type TP53. Functional studies demonstrated that CCDC8 promotes tumor cell proliferation, migration, and survival in vitro, and enhances tumor growth in vivo. Mechanistically, CCDC8 interacts with the E3 ubiquitin ligase scaffold protein CUL7, facilitating proteasome-dependent degradation of P53, thereby suppressing its downstream effectors such as P21 and BAX. Pharmacological inhibition of neddylation with MLN4924 restored P53 levels and reversed the oncogenic effects of CCDC8 both in vitro and in vivo. Together, these findings highlight a novel mechanism of P53 regulation in bladder cancer, position CCDC8 as a potential biomarker and therapeutic target, and suggest a molecular link between chronic bladder inflammation and malignant transformation.

DOI: https://doi.org/10.1038/s41388-026-03688-x