Nicolas Anselmino, Pablo Sanchis, Juan Bizzotto, Estefania Labanca, Jiabin Dong, Peter D A Shepherd, Jun Yang, Elba S Vazquez, Joaquin Mateo, Geraldine Gueron, Christopher J Logothetis
{"title":"Role of the cross-regulation between Wnt pathway activation and androgen receptor signaling in prostate cancer treatment resistance.","authors":"Nicolas Anselmino, Pablo Sanchis, Juan Bizzotto, Estefania Labanca, Jiabin Dong, Peter D A Shepherd, Jun Yang, Elba S Vazquez, Joaquin Mateo, Geraldine Gueron, Christopher J Logothetis","doi":"10.1038/s41418-026-01732-7","DOIUrl":"https://doi.org/10.1038/s41418-026-01732-7","url":null,"abstract":"<p><p>Prostate cancer (PCa) is a biologically heterogeneous disease that frequently progresses to castration-resistant prostate cancer (CRPC), a challenging clinical stage. The underlying mechanisms driving CRPC progression and resistance to androgen receptor (AR) signaling inhibition (ARSI) remain incompletely understood. Emerging evidence implicates the canonical Wnt pathway as a key contributor to CRPC progression. This study elucidates the role of Wnt pathway activation in mediating resistance to ARSI and identifies a robust molecular signature for predicting treatment outcomes. By integrating genomic and transcriptomic data from PCa patients, patient-derived xenografts (PDXs), and experimental models harboring or not Wnt-activating mutations, we performed differential expression analysis, unsupervised clustering, survival, and viability analysis to assess Wnt/β-catenin pathway activation and its interaction with AR signaling. A specific Wnt transcriptional signature (AXIN2, RNF43, ZNRF3, NKD1) was found to reliably reflect pathway activation in advanced PCa. AR was found to suppress mutation-driven Wnt signaling, which was upregulated upon AR inhibition, contributing to treatment resistance. Targeting β-catenin interactions with co-activators p300/CBP using selective inhibitors (IQ-1 and ICG-001) effectively mitigated Wnt-driven ARSI resistance, restoring sensitivity to therapy in preclinical models. Thus, canonical Wnt pathway activation emerges as a critical mediator of resistance to ARSI in CRPC. The identified Wnt signature holds potential as a biomarker for predicting and monitoring therapeutic outcomes. Concurrent targeting of AR and Wnt signaling represents a promising strategy to overcome treatment resistance, particularly in patients with Wnt-activating mutations.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qianming Du, Yuxiang Fei, Tao Li, Deju Wang, Sheng Hu, Ya Yang, Wenlian Tang, Xu Zhang, Hongting Diao, Chao Liu
{"title":"Targeting CAFs-derived PCSK6 inhibits redistribution of PD-L1 and restores response of CD8<sup>+</sup>T cells against colorectal cancer.","authors":"Qianming Du, Yuxiang Fei, Tao Li, Deju Wang, Sheng Hu, Ya Yang, Wenlian Tang, Xu Zhang, Hongting Diao, Chao Liu","doi":"10.1038/s41418-026-01736-3","DOIUrl":"https://doi.org/10.1038/s41418-026-01736-3","url":null,"abstract":"<p><p>Carcinoma-associated fibroblasts (CAFs) are core components of the tumor microenvironment, which contribute to tumor initiation and progression through mediating immune suppression. In this study, eight activated CAF subpopulations were identified by single-cell sequencing (scRNA-seq). A specific subtype of CAFs, characterized by PCSK6 expression, strengthened PD-L1 membrane distribution, which contributed to the cytotoxic CD8<sup>+</sup>T cells exhaustion, subsequently promoting the progression of colorectal cancer (CRC). PCSK6 interacting with ACVR1B on CRC cell surface, promoting the acetylation modification of PD-L1 via acetyltransferase p300, followed by strengthened PD-L1 membrane distribution. Loss of PCSK6/ACVR1B signaling in tumor stroma enhanced the intratumoral infiltration and activation of CD8<sup>+</sup>T cells, alleviated growth of CRC and conferred survival advantage in tumor-bearing mice. Moreover, the membrane level of PD-L1 was mediated by the membrane transport complex Rab8/EHBP1L1. Our finding suggested PCSK6/ACVR1B-p300-Rab8/EHBP1L1-PD-L1 signaling axis is significantly activated by CAFs-derived PCSK6, which may offer mechanism interpretation for CAFs mediated CRC immune escape and suggest potential mechanism-based therapeutic strategies for ACVR1B antagonist.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"HECT ubiquitin ligases as regulators of inflammatory signalling.","authors":"Diva Sinha, Sonia S Shah, Sharad Kumar","doi":"10.1038/s41418-026-01740-7","DOIUrl":"https://doi.org/10.1038/s41418-026-01740-7","url":null,"abstract":"<p><p>Ubiquitination is a versatile post-translational modification that regulates protein stability, localisation and signalling. By modifying a wide range of substrates, ubiquitination controls key physiological processes, including inflammatory responses, which are the focus of this article. Precise regulation of inflammatory signalling is essential, as insufficient activation compromises host defence while sustained signalling contributes to chronic inflammation, autoimmunity and degenerative disease. Within the ubiquitin system, E3 ligases confer substrate specificity and influence ubiquitin chain topology, thereby directing downstream protein fate and signalling outcomes. HECT family E3 ligases form transient E3~ubiquitin thioester intermediates that enable controlled ubiquitin transfer to target proteins. Through this activity, they regulate the strength and duration of inflammatory signalling pathways. In this review, we discuss HECT E3 ubiquitin ligases involved in inflammation and how their ubiquitin-modifying functions influence immune signalling and inflammatory disease progression.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
W Malorni, M G Farrace, P Matarrese, A Tinari, L Ciarlo, P Mousavi-Shafaei, M D'Eletto, G Di Giacomo, G Melino, L Palmieri, C Rodolfo, M Piacentini
{"title":"Editorial Expression of Concern: The adenine nucleotide translocator 1 acts as a type 2 transglutaminase substrate: implications for mitochondrial-dependent apoptosis.","authors":"W Malorni, M G Farrace, P Matarrese, A Tinari, L Ciarlo, P Mousavi-Shafaei, M D'Eletto, G Di Giacomo, G Melino, L Palmieri, C Rodolfo, M Piacentini","doi":"10.1038/s41418-026-01741-6","DOIUrl":"https://doi.org/10.1038/s41418-026-01741-6","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patricia Wilson, Vishakha Vishwakarma, Rebecca Norcross, Kashmira Khaire, Van N. Pham, Brant M. Weinstein, Hyun Min Jung, Emilia Galperin
{"title":"Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses","authors":"Patricia Wilson, Vishakha Vishwakarma, Rebecca Norcross, Kashmira Khaire, Van N. Pham, Brant M. Weinstein, Hyun Min Jung, Emilia Galperin","doi":"10.1038/s41418-026-01730-9","DOIUrl":"https://doi.org/10.1038/s41418-026-01730-9","url":null,"abstract":"An interplay of growth factors and signaling pathways governs the development and maintenance of lymphatic vasculature, ensuring proper fluid homeostasis and immune function. Disruption of these regulatory mechanisms can lead to congenital lymphatic disorders and contribute to various pathological conditions. However, the mechanisms underlying the molecular regulation of these processes remain elusive. Here, we reveal a critical and previously unappreciated role for the signaling scaffold protein Shoc2 in lymphangiogenesis. We demonstrate that loss of Shoc2 results in near-complete loss of lymphatic vasculature in vivo and senescence of lymphatic endothelial cells in vitro. Mechanistically, Shoc2 is required for balancing signaling through the ERK1/2 pathway, and its loss results in increased mTORC1 signaling. This dysregulation impairs mitochondrial respiration and triggers an IRF/IFN-II response, ultimately leading to cellular senescence. Strikingly, expression of the Noonan Syndrome with Loose anagen Hair (NSLH)-causing Shoc2 variant S2G phenocopies the effects of Shoc2 loss. Together, these studies establish the critical role of Shoc2 in lymphangiogenesis and uncover a novel mechanistic link between Shoc2 signaling, mitochondrial function, innate immune response, and lymphatic development, with significant implications for Ras-pathway-related congenital disorders.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"21 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147630944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yu Yang, Yue Wang, Yang Wang, Erpeng Wu, Hao Chen, Liming Sun, Chi Zhang, Shuhui Cao, Jingwen Li, Huiping Qiang, Lincheng Zhang, Yuqing Lou, Rong Qiao, Shenao Zhou, Yan Zhou, Runbo Zhong, Hua Zhong
{"title":"RIPK3 sequentially recruits MLKL and RIPK1 to induce PANoptosis and chemokine production.","authors":"Yu Yang, Yue Wang, Yang Wang, Erpeng Wu, Hao Chen, Liming Sun, Chi Zhang, Shuhui Cao, Jingwen Li, Huiping Qiang, Lincheng Zhang, Yuqing Lou, Rong Qiao, Shenao Zhou, Yan Zhou, Runbo Zhong, Hua Zhong","doi":"10.1038/s41418-026-01737-2","DOIUrl":"https://doi.org/10.1038/s41418-026-01737-2","url":null,"abstract":"<p><p>Receptor-interacting protein kinase 3 (RIPK3) has emerged as a central player in necroptosis and apoptosis activation in specific scenarios, concurrently modulating inflammatory responses. Here, we reveal that direct activation of RIPK3 concomitantly triggers mixed lineage kinase domain-like (MLKL) phosphorylation, caspase activation, and gasdermin cleavage within individual cells, inducing PANoptotic cell death. This process is orchestrated by the formation of RIPK3-MLKL-RIPK1-FADD-Caspase-8 complexes on progressively polymerized RIPK3 homo-aggregates, achieved through sequential recruitment dictated by the differential affinities of MLKL and Receptor-interacting protein kinase 1 (RIPK1) for distinct oligomeric states of RIPK3. In this process, MLKL- and GSDMD-mediated membrane rupture is respectively inhibited by Caspase-3-dependent cleavage of RIPK3 and GSDMD cleavage, while the pro-necrotic kinase activity of RIPK3 impedes RIPK1 recruitment and attenuates caspase activation. Cross-regulation between pathways results in unique cellular morphology, altered damage-associated molecular patterns (DAMPs) release profiles and distinct chemokine secretion paradigms that differ fundamentally from classical necroptosis, apoptosis and pyroptosis. This work highlights a common mechanism unveiling RIPK3 as a multimolecular platform to modulate and integrate different programmed cell death (PCD) pathways, thus providing a framework for targeting inflammatory cell death in disease.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Doo Sin Jo, Na Yeon Park, Ae-Kyeong Kim, Sunhoe Bang, Yong Hwan Kim, Ji-Eun Bae, Kyunghee Noh, Jeong-Hoon Kim, Min Jae Lee, Seong-Kyu Choe, Peter K Kim, Jongkyeong Chung, Kyu-Sun Lee, Dong-Hyung Cho
{"title":"PINK1 and STUB1 pathway orchestrates peroxisomal selective autophagy by PEX13 depletion.","authors":"Doo Sin Jo, Na Yeon Park, Ae-Kyeong Kim, Sunhoe Bang, Yong Hwan Kim, Ji-Eun Bae, Kyunghee Noh, Jeong-Hoon Kim, Min Jae Lee, Seong-Kyu Choe, Peter K Kim, Jongkyeong Chung, Kyu-Sun Lee, Dong-Hyung Cho","doi":"10.1038/s41418-026-01726-5","DOIUrl":"https://doi.org/10.1038/s41418-026-01726-5","url":null,"abstract":"<p><p>Peroxisomes are dynamic organelles essential for lipid metabolism, oxidative balance, and cellular stress responses. Their dysfunction contributes to various diseases, including metabolic and neurodegenerative disorders. Selective autophagy, or pexophagy, preserves peroxisomal quality by removing damaged or excess peroxisomes. Here, we propose a novel ATM-PINK1-STUB1-ABCD3-SQSTM1 signaling cascade that orchestrates pexophagy in response to peroxisomal impairment. Through siRNA screening, we find that PINK1 is a key regulator of pexophagy induced by PEX13 depletion. PINK1 phosphorylates STUB1, enhancing its E3 ligase activity to ubiquitinate ABCD3, which in turn recruits SQSTM1 for peroxisomal degradation. We further identify that ATM activates PINK1 under peroxisomal stress, linking cellular stress signaling to organelle quality control. These findings provide new insights into the molecular mechanisms underlying peroxisome turnover and may have implications for therapeutic strategies targeting diseases related to peroxisomal dysfunction.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction: The inhibitory effect of compound ChlA-F on human bladder cancer cell invasion can be attributed to its blockage of SOX2 protein.","authors":"Xiaohui Hua, Maowen Huang, Xu Deng, Jiheng Xu, Yisi Luo, Qipeng Xie, Jiawei Xu, Zhongxian Tian, Jingxia Li, Junlan Zhu, Chao Huang, Qin-Shi Zhao, Haishan Huang, Chuanshu Huang","doi":"10.1038/s41418-026-01721-w","DOIUrl":"https://doi.org/10.1038/s41418-026-01721-w","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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