Cellular signalling最新文献

{"title":"Ingenol ameliorates silicosis via targeting the PTGS2/PI3K/AKT signaling axis: Implications for therapeutic intervention","authors":"Yifan Jing ,&nbsp;Ying Bai ,&nbsp;Chao Liang ,&nbsp;Yafeng Liu ,&nbsp;Jiawei Zhou ,&nbsp;Jianqiang Guo ,&nbsp;Xiaolong Cai ,&nbsp;Xiaofei Hu ,&nbsp;Yujing Fang ,&nbsp;Xuansheng Ding ,&nbsp;Jing Wu ,&nbsp;Dong Hu","doi":"10.1016/j.cellsig.2025.111780","DOIUrl":"10.1016/j.cellsig.2025.111780","url":null,"abstract":"<div><div>Silicosis, formerly known as silico, is an irreversible disease caused by prolonged inhalation of substantial amounts of free crystalline silica dust, characterized by pulmonary inflammation and extensive nodular fibrosis. The etiology of the disease remains unclear, which currently hinders the development of effective therapeutic drugs and interventions. Ingenol (Ing), a terpenoid active ingredient found in plants of the Euphorbiaceae family, including the entire herb of <em>Euphorbia helioscopia</em>, <em>Euphorbia kansui</em>, or <em>Euphorbia lathyris</em>, demonstrates significant anti-inflammatory and antiviral activities. In this study, we identified and confirmed that Ingenol can significantly ameliorate silicosis induced by silica dioxide by inhibiting the PTGS2/PI3K/AKT signaling pathway. In vivo, Ingenol improves pulmonary respiratory function and reduces inflammation and fibrosis in a murine model of CS-induced silicosis. In vitro, Ingenol inhibits the expression of cellular factors associated with inflammation and fibrosis, as well as macrophage apoptosis and fibroblast migration. Furthermore, it can modulate the expression of fibrosis-related proteins, thereby inhibiting CS-induced fibrotic responses. Mechanistically, a combination of bioinformatics, network pharmacology, and experimental validation indicates that Ingenol mitigates the progression of silicosis by modulating the PTGS2/PI3K/AKT signaling pathway. In summary, these findings suggest that Ingenol is a potential candidate for the treatment of silicosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111780"},"PeriodicalIF":4.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis contributed to endoplasmic reticulum stress in preterm birth by targeting LHX1 and IRE-1","authors":"Liyin Qiu ,&nbsp;Hui Liu ,&nbsp;Shali Chen ,&nbsp;Yiting Wu ,&nbsp;Jianying Yan","doi":"10.1016/j.cellsig.2025.111777","DOIUrl":"10.1016/j.cellsig.2025.111777","url":null,"abstract":"<div><div>Preterm birth (PTB) significantly contributed to neonatal mortality, emphasizing the need for a detailed understanding of its pathogenesis. This study aimed to explore the involvement of ferroptosis, an iron-dependent cell death process, in PTB and investigated the possible crosstalk with endoplasmic reticulum stress (ERS). First, we explored the occurrence of ferroptosis in placenta samples from PTB parturients. Then we established a ferroptosis cell model was established by subjecting trophoblast cells to hypoxia/reoxygenation (H/R), and found the ERS was induced in H/R exposed cells and was attenuated by ferroptosis inhibition using Fer-1, suggesting that ferroptosis could induce ERS. Meanwhile, we also induced ERS in trophoblast cells via tunicamycin (TM) treatment. Ferroptosis inhibition with Fer-1 alleviated TM-induced ER stress. TM treatment reduced trophoblast cell viability and migration while promoted apoptosis and autophagy, effects that were reversed by ferroptosis inhibition. Thus, targeting ferroptosis might help mitigate ER stress-related pathophysiological changes in PTB. Mechanically, we found two ERS mediators LIM homeobox 1 (LHX1)/Inositol-requiring enzyme 1 (IRE-1) were also upregulated in H/R treated cells. Silencing LHX1 or IRE-1 was demonstrated to reverse the H/R-induced ferroptosis. Additionally, rescue assays further revealed that LHX1 promoted ferroptosis by regulating IRE-1. In conclusion, ferroptosis contributed to ERS and was critically involved in PTB, highlighting the LHX1/IRE-1 axis as a promising therapeutic target for mitigating ferroptosis-related complications. These findings offered a foundation for innovative interventions in preterm birth.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111777"},"PeriodicalIF":4.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of SLC2A1 is upregulated in a mouse model of age-related hearing loss","authors":"Jiali Liu ,&nbsp;Haisen Peng ,&nbsp;Yuehui Liu,&nbsp;Chunhua Li,&nbsp;Zhilin Zhang,&nbsp;Shuihua Hu,&nbsp;Wen Xie","doi":"10.1016/j.cellsig.2025.111776","DOIUrl":"10.1016/j.cellsig.2025.111776","url":null,"abstract":"<div><h3>Background</h3><div>Age-related hearing loss (ARHL) is a common issue associated with aging. One of the typical causes of hearing loss is the irreversible death of hair cells. In addition, oxidative stress contributes to ARHL. However, the underlying molecular mechanism in ARHL is not well understood.</div></div><div><h3>Methods</h3><div>The ARHL samples were from GSE153882 datasets of the Gene Expression Omnibus database. The Limma R-package was used to identify differentially expressed genes. The hub gene was obtained <em>via</em> intersection of oxidative stress genes and cuproptosis genes. Hearing function was measured using the auditory brainstem response (ABR). Western blot and immunofluorescence were used to examine solute carrier family 2 member 1 protein (SLC2A1), dihydrolipoyl transacetylase (DLAT) an dihydrolipoamide dehydrogenase (DLD) <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Results</h3><div>Oxidative stress gene SLC2A1 (also named GLUT1) is related to cuproptosis gene in age-related hearing loss. In the ARHL mice model, SLC2A1, DLAT and DLD were elevated. The ABR recordings showed that SLC2A1 knockdown lowered the average thresholds of mice. Knockdown SLC2A1 alleviated DLAT and DLD <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>Our findings highlight SLC2A1 as an essential driver of cuproptosis and ARHL. Knockdown SLC2A1 suppresses ARHL progression <em>via</em> inhibiting cuproptosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111776"},"PeriodicalIF":4.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP22 promotes angiotensin II-induced podocyte injury by deubiquitinating and stabilizing HMGB1","authors":"Zhuan Peng ,&nbsp;Xiaoxiao Huang ,&nbsp;Yangbin Pan ,&nbsp;Weiwei Li ,&nbsp;Hongtu Hu ,&nbsp;Xinghua Chen ,&nbsp;Zongwei Zhang ,&nbsp;Jijia Hu ,&nbsp;Yue Qi ,&nbsp;Wenjie Chen ,&nbsp;Xiaofei Cui ,&nbsp;Hongyan Liu ,&nbsp;Wei Liang ,&nbsp;Guohua Ding ,&nbsp;Zhaowei Chen","doi":"10.1016/j.cellsig.2025.111771","DOIUrl":"10.1016/j.cellsig.2025.111771","url":null,"abstract":"<div><h3>Background</h3><div>Chronic kidney disease (CKD) remains a significant global health burden, with hypertensive nephropathy (HN) as one of its primary causes. Podocyte injury is a key factor in the progression of CKD. However, the molecular mechanisms underlying angiotensin II-induced podocyte injury remain incompletely understood. Ubiquitin-specific protease 22 (USP22) has been reported to facilitate a range of cellular processes, including cell proliferation and apoptosis. However, the role of USP22 in HN pathogenesis is unclear.</div></div><div><h3>Methods</h3><div>The expression of USP22 was assessed in kidney samples from hypertensive nephropathy patients, angiotensin II-induced hypertensive nephropathy mouse models, and cultured podocytes treated with angiotensin II. Podocyte-specific USP22 knockout mice were used to investigate the effects of USP22 deletion on podocyte injury and inflammation.</div></div><div><h3>Results</h3><div>USP22 expression was significantly upregulated in kidneys of HN patients, angiotensin II-induced mouse models, and cultured podocytes. Podocyte-specific deletion of USP22 markedly reduced angiotensin II-induced podocyte injury and inflammatory responses. Furthermore, we identified high-mobility group box protein 1 (HMGB1) as a protein that interacts with USP22. USP22 deubiquitinated and stabilized HMGB1 through K48-linked ubiquitination. Downregulation of USP22 expression improved kidney function and pathological changes in HN by promoting HMGB1 degradation.</div></div><div><h3>Conclusion</h3><div>This study identifies USP22 as a key regulator of angiotensin II-induced podocyte injury and inflammation through its interaction with HMGB1. Our findings revealed that following glomerular injury, damage and shedding of tubular cells also occurred. Targeting the USP22-HMGB1 axis offers a promising therapeutic strategy for treating hypertensive nephropathy and other types of CKD.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111771"},"PeriodicalIF":4.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EOGT knockdown promotes ferroptosis and inhibits hepatocellular carcinoma proliferation by regulating SLC7A11 via HEY1","authors":"Zhe Yu ,&nbsp;Jing Luo ,&nbsp;Wen An ,&nbsp;Herui Wei ,&nbsp;Aqian Song ,&nbsp;Yuanpeng Mao ,&nbsp;Mengqi Li ,&nbsp;Lingling He ,&nbsp;Fan Xiao ,&nbsp;Qi Gao ,&nbsp;Hongshan Wei","doi":"10.1016/j.cellsig.2025.111772","DOIUrl":"10.1016/j.cellsig.2025.111772","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by a complex molecular landscape. EGF Domain Specific <em>O-</em>linked β-<em>N-</em>acetylglucosamine transferase (EOGT) functions as an <em>O-</em>GlcNAc transferase with specific activity towards proteins containing epidermal growth factor (EGF) repeats. Although it is known to potentially play an oncogenic role in HCC, the exact mechanisms remain unclear. Induction of ferroptosis is a primary mechanism by which anticancer drugs such as sorafenib treat HCC. This study aimed to elucidate the expression profile of EOGT in HCC and its relationship with ferroptosis, as well as to investigate the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>Utilizing bioinformatics resources, we explored the potential role of EOGT in HCC. The effects of EOGT on HCC cell behavior were examined using cell models and subcutaneous xenograft models in nude mice. Further insights into the molecular mechanisms were obtained through RNA-seq in cell models, hydrodynamic modeling in mice, Western blotting, chromatin immunoprecipitation (ChIP) sequencing, and dual-luciferase reporter assays to analyze the interaction between HEY1 and SLC7A11. Multiple validation steps were employed to thoroughly investigate the roles of these factors in the regulation of ferroptosis in HCC.</div></div><div><h3>Results</h3><div>Our findings revealed that EOGT is upregulated in HCC and correlates with poor prognosis and drug resistance. Knockdown of EOGT inhibited HCC cell proliferation and enhanced sensitivity to ferroptosis by downregulating SLC7A11, a process mediated by HEY1. These results were confirmed by cell viability assays, quantitative real-time PCR (qPCR), Western blotting, and dual-luciferase reporter gene assays.</div></div><div><h3>Conclusions</h3><div>EOGT promotes HCC proliferation and inhibits ferroptosis by modulating the HEY1-SLC7A11 axis, suggesting a potential therapeutic target for HCC treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111772"},"PeriodicalIF":4.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of DJ-1 induces TFAM secretion from cancer cells to suppress tumor growth via promoting M1 macrophage polarization","authors":"Caiqi Xu ,&nbsp;Yaoyao Wu ,&nbsp;Sui Yang ,&nbsp;Xuechun Zhao ,&nbsp;Hao Zhang ,&nbsp;Yunwen Yan ,&nbsp;Jiemin Zhao ,&nbsp;Wei Wei ,&nbsp;Qian Meng ,&nbsp;Yujuan Wang ,&nbsp;Rui Zhang","doi":"10.1016/j.cellsig.2025.111765","DOIUrl":"10.1016/j.cellsig.2025.111765","url":null,"abstract":"<div><div>DJ-1, also known as PARK7 (Parkinson's disease protein 7), which is involved in cell viability, apoptosis, transcriptional regulation, and oxidative stress adaptation, is also involved in the pathogenesis of various human diseases including carcinogenesis. Here, we aimed to determine the novel mechanism by which DJ-1 inhibition suppresses tumor growth. Our results showed that DJ-1 knockdown in cancer cells promoted the secretion of a significantly larger amount of mitochondrial transcription factor A (TFAM) into the cell culture medium. DJ-1 knockdown promotes p53 translocation to the mitochondria and stimulates the intrinsic mitochondrial apoptosis pathway, resulting in TFAM release. Moreover, DJ-1 knockdown induced the downregulation of sirtuin 3 (SIRT3), which increased the acetylation of TFAM and triggered its release. Furthermore, we found that extracellular TFAM played a critical role in antitumor activity by upregulating the expression of chemokine (C<img>C motif) ligand 4 (CCL4) and chemokine (C-X-C motif) ligand 5 (CXCL5) in cancer cells, contributing to the promotion of M1 macrophage polarization in the tumor microenvironment (TME). Finally, we confirmed that the DJ-1 inhibitor suppressed tumor growth by increasing TFAM release from cancer cells and M1 macrophage polarization in vivo. These findings indicate that the depletion of DJ-1 stimulates apoptosis-dependent TFAM secretion that triggers M1 macrophage polarization, indicating a new therapeutic strategy by interfering with the DJ-1 function in cancer therapy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111765"},"PeriodicalIF":4.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rescuing fertility: Itaconic acid prevents ovarian damage through NRF2-mediated pyroptosis pathways in diminished ovarian reserve models","authors":"Ling Yang ,&nbsp;Wenya Mo ,&nbsp;Lei Xin ,&nbsp;Mingzhao Zhang ,&nbsp;Kegong Chen ,&nbsp;Xiaohui Guo ,&nbsp;Jing Zhang ,&nbsp;Biao Yu","doi":"10.1016/j.cellsig.2025.111766","DOIUrl":"10.1016/j.cellsig.2025.111766","url":null,"abstract":"<div><h3>Background</h3><div>Diminished ovarian reserve (DOR) is a major cause of infertility, often triggered by inflammation and oxidative stress. Pyroptosis, a form of programmed cell death, has been implicated in DOR pathogenesis. Itaconic acid (IA), an endogenous metabolite, is known for its anti-inflammatory and antioxidant properties. This study aimed to explore whether IA could alleviate lipopolysaccharide (LPS)-induced DOR in mice by inhibiting pyroptosis through the NRF2 pathway.</div></div><div><h3>Methods</h3><div>A DOR mouse model was established by administering LPS for 5 consecutive days, followed by IA treatment. Ovarian function was assessed by follicle count and hormone levels. Inflammatory markers, oxidative stress, and pyroptosis-related proteins were evaluated in both <em>in vivo</em> and <em>in vitro</em> models. The molecular mechanism was further investigated using inhibitors and molecular docking studies.</div></div><div><h3>Results</h3><div>IA significantly improved ovarian function in LPS-induced DOR mice by increasing the number of follicles and normalizing hormone levels. IA also reduced inflammation, oxidative stress, and pyroptosis, as evidenced by lower expression of NLRP3, cleaved-caspase-1, and N-GSDMD, while increasing NRF2 expression. <em>In vitro</em>, IA enhanced granulosa cell (GC) viability, reduced reactive oxygen species (ROS), and decreased pyroptosis in LPS-treated GCs. Additionally, the beneficial effects of IA were mediated via the NRF2 pathway, as NRF2 inhibition (ML385) reversed these improvements. Additionally, we identified GSDMD as a downstream target of IA, with inhibition of GSDMD ameliorating DOR progression and inflammatory responses.</div></div><div><h3>Conclusion</h3><div>IA alleviates LPS-induced DOR by reducing inflammation, oxidative stress, and pyroptosis through activation of the NRF2 signaling and direct inhibition of the GSDMD pathway. These findings suggest that IA may serve as a potential therapeutic agent for improving ovarian reserve and fertility.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111766"},"PeriodicalIF":4.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of miR-27a-3p induces endothelial injury and senescence and its significance in the development of coronary heart disease","authors":"Chong-Yang Song ,&nbsp;Hai-Zhen Huang ,&nbsp;Ting-Ting Yan ,&nbsp;Chen-Xi Cui ,&nbsp;Hua-Yu Wu ,&nbsp;Jing Chen ,&nbsp;Jun-Hua Peng ,&nbsp;Ning-Yuan Chen ,&nbsp;Jun Tang ,&nbsp;Shang-Ling Pan","doi":"10.1016/j.cellsig.2025.111759","DOIUrl":"10.1016/j.cellsig.2025.111759","url":null,"abstract":"<div><div>miR-27a-3p is a multifunctional miRNA that plays a critical role in the process of angiogenesis. However, its specific effect on coronary heart disease (CHD), particularly on the regulation of downstream molecules and the resulting impact on endothelial cell injury, has not yet been fully elucidated. This study aimed to explore the relationship between miR-27a-3p and CHD and its underlying mechanical molecular pathways in CHD patients and modeled endothelial cells with techniques such as RT-qPCR, RNA sequencing and bioinformatics. Consequently, the expression of miR-27a-3p was significantly decreased in CHD patients. In endothelial cells, overexpression of miR-27a-3p was observed to decrease malonaldehyde, gamma H2A histone family member X and interleukin 6 while increased superoxide dismutase, thus reduced endothelial injury and senescence. RNA sequencing and bioinformatics revealed glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D) as a target gene of miR-27a-3p, and dual luciferase assays confirmed the direct binding of miR-27a-3p to the 3’UTR of GRIN2D. Subsequent validation experiments demonstrated that miR-27a-3p inhibited the protein expression of GRIN2D and PKC and suppressed the activation of the MAPK/ERK signaling pathway by reduced downstream MEK and ERK phosphorylation, leading to enhanced endothelial apoptosis. In conclusion, miR-27a-3p played a crucial role in regulating endothelial cell dysfunction which may trigger coronary atherosclerosis and CHD by targeting GRIN2D in the PKC/MEK/ERK signaling pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111759"},"PeriodicalIF":4.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a new micropeptide altKLF4 derived from KLF4 that influences myeloma chemotherapeutic sensitivity","authors":"Ruosi Yao ,&nbsp;Yindi Zeng ,&nbsp;Yaxin Zhang ,&nbsp;Xu Cao ,&nbsp;Jiwei Mao ,&nbsp;Wenjing Li ,&nbsp;Kailin Xu ,&nbsp;Linlin Liu","doi":"10.1016/j.cellsig.2025.111767","DOIUrl":"10.1016/j.cellsig.2025.111767","url":null,"abstract":"<div><div>Multiple myeloma (MM) is a common yet incurable hematological malignancy characterized by bone marrow infiltration. A major clinical challenge is the resistance to chemotherapy, highlighting the urgent need to better understand the molecular mechanisms underlying chemotherapeutic resistance to available drugs. Recent studies have emphasized the role of micropeptides in solid tumors and leukemia, but their functions in MM remain unclear. In this study, we identified a novel micropeptide, altKLF4, derived from the transcription factor KLF4, which is highly expressed in newly diagnosed myeloma patient samples. We found that ectopic expression of altKLF4 interfered with chemotherapy sensitivity induced by proteasome inhibitors in myeloma cells. Additionally, confocal microscopy and transcriptome sequencing revealed that altKLF4 co-localizes with the mitochondrial inner marker TOMM20 and participates in mitochondria-related biological processes, suggesting that altKLF4 partially localizes to the mitochondria. Mitochondria may also play a role in regulating ferroptosis. Our results further demonstrated that altKLF4 inhibited drug sensitivity and ferroptosis induced by the GPX4 inhibitor RSL3 in multiple myeloma cells through a direct interaction with GPX4. <em>In vivo</em> experiments showed that RSL3 significantly suppressed primary myeloma growth, which could be rescued by the micropeptide altKLF4. Taken together, our study identifies altKLF4 as a novel micropeptide that serves as a potential biomarker for chemotherapeutic resistance in multiple myeloma, offering insights for diagnosis and management of drug-resistant MM.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111767"},"PeriodicalIF":4.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered nanovesicles targeting SERPINE1 overcome temozolomide resistance in glioblastoma","authors":"Jianping Wen ,&nbsp;Dongxu Wu ,&nbsp;Yi Le ,&nbsp;Zonghua Yin ,&nbsp;Minglong Chen ,&nbsp;Yulong Shen ,&nbsp;Xia Wu ,&nbsp;Kebo Liu ,&nbsp;Kun Luo ,&nbsp;Zhicheng Shu ,&nbsp;Qingxia Shu ,&nbsp;Dongsheng Ouyang","doi":"10.1016/j.cellsig.2025.111763","DOIUrl":"10.1016/j.cellsig.2025.111763","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with limited treatment options due to its resistance to temozolomide (TMZ). This study explores a novel therapeutic approach using engineered cell membrane nanovesicles loaded with SERPINE1 inhibitors to combat TMZ resistance. High-throughput sequencing identified pivotal genes associated with resistance, while the nanovesicles demonstrated excellent stability and the ability to cross the blood-brain barrier. Functional assays revealed significant suppression of GBM cell viability, migration, and invasion, accompanied by reduced expression of SERPINE1 and VEGF, suggesting inhibition of angiogenesis and tumor progression. These findings highlight the potential of SERPINE1-targeted nanovesicles as an innovative and effective strategy for overcoming TMZ resistance in GBM.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111763"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}