Cell. Signal. [JOURNAL]
Sun
200 papers
CLDN6 inhibits breast cancer growth by inducing autophagic cell death through SOX4 m6A modification.
Jin Q, Liang Y, Qu H … +5 more , Qi D, Dong Y, Sun M, Liu Y, Quan C
Cell Signal · 2026 Sep · PMID 42070760 · Publisher ↗
Breast cancer is a life-threatening malignancy with subtle early symptoms, necessitating novel biomarkers and mechanistic insights. The tight junction protein CLDN6 plays a tumor-suppressive role in breast cancer, yet it...
Breast cancer is a life-threatening malignancy with subtle early symptoms, necessitating novel biomarkers and mechanistic insights. The tight junction protein CLDN6 plays a tumor-suppressive role in breast cancer, yet its underlying molecular mechanisms remain incompletely understood. Herein, we demonstrate that CLDN6 suppresses breast cancer growth by inducing autophagic cell death through METTL14-mediated m6A modification of SOX4 mRNA. Mechanistically, CLDN6 sequesters PDLIM2 at the cell membrane, reducing nuclear PDLIM2-mediated RelA ubiquitination. Accumulated RelA transcriptionally upregulates METTL14, enhancing SOX4 mRNA m6A modification and degradation, which attenuates PI3K/Akt signaling and triggers autophagic cell death. Moreover, protein expression analysis in breast cancer tissues and bioinformatics analyses reveal an association between the CLDN6/METTL14/SOX4 axis and patient prognosis. These findings identify the CLDN6/METTL14/SOX4 axis as a promising prognostic signature and potential therapeutic target for breast cancer, highlighting the interplay among tight junction protein, epigenetic modification, and autophagic cell death as a conceptual basis for multi-targeted therapeutic strategies.
P-Rex Rac-GEFs.
Welch HCE
Cell Signal · 2026 Sep · PMID 42069100 · Publisher ↗
The P-Rex family proteins P-Rex1 and P-Rex2 are Dbl-type guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases upon synergistic stimulation by PIP and Gβγ, acting as coincidence detectors for PI3K an...
The P-Rex family proteins P-Rex1 and P-Rex2 are Dbl-type guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases upon synergistic stimulation by PIP and Gβγ, acting as coincidence detectors for PI3K and GPCR signalling. P-Rex Rac-GEFs control physiological responses ranging from inflammation, innate and adaptive immunity to GPCR trafficking, glucose homeostasis, and the function of the vascular endothelium, nervous system, and adipose tissue. P-Rex2 also increases PI3K-signalling through its catalysis-independent inhibition of the tumour suppressor PTEN. Deregulated levels of P-Rex1 are linked to fibrotic diseases, asthma, and autism spectrum disorders, and both P-Rex1 and P-Rex2 are deregulated in metabolic diseases. Upregulation of P-Rex1 and P-Rex2 as well as activating P-Rex2 mutations also occur in many types of cancer, including breast, prostate, lung, liver and colorectal cancer, as well as in melanoma and glioma. and contribute to tumour growth or metastasis depending on the P-Rex protein and cancer type. Deregulation of P-Rex1 in cancer typically promotes tumour growth or metastasis, whereas upregulation or mutation of P-Rex2 in cancer is mostly associated with tumour growth. Recently, structural data have increased our understanding of P-Rex regulation, the first P-Rex inhibitors have been developed, and GEF-activity independent functions of P-Rex proteins in GPCR trafficking, neutrophil-responses, innate immunity, and glucose homeostasis have been described. This review summarises the P-Rex literature from the discovery of the P-Rex protein family in 2002 to the present, with a focus on recent advances.
JOSD2 deubiquitinating enzyme: Structure, function, and potential as a therapeutic target.
Li Z, Hu J, Wang L … +4 more , Liu Y, Teng J, Wei S, Wang L
Cell Signal · 2026 Sep · PMID 42069099 · Publisher ↗
BACKGROUND: Ubiquitination, a central post-translational mechanism, shapes the amplitude and duration of cellular signalling. Josephin domain-containing 2 (JOSD2), a Machado-Joseph disease (MJD) family deubiquitinase, el...
BACKGROUND: Ubiquitination, a central post-translational mechanism, shapes the amplitude and duration of cellular signalling. Josephin domain-containing 2 (JOSD2), a Machado-Joseph disease (MJD) family deubiquitinase, eliminates ubiquitin moieties from ubiquitin-conjugated substrates and tunes proteostasis and signalling outputs. Emerging evidence links aberrant JOSD2 activity to diverse pathological states. MAIN BODY: This review, aims to summarize the current data regarding of JOSD2 as a regulatory node in ubiquitin-dependent signalling and discuss the role of its dysregulation in malignancies through interconnected mechanisms, including metabolic rewiring, rewiring of oncogenic signalling circuits, and altered therapeutic responses that promote resistance. Furthermore, the context-dependent roles of JOSD2 beyond cancer emphasized, with reported pathogenic or protective functions in cardiovascular disorders and inflammatory bowel disease. CONCLUSION: The literature highlights JOSD2 as a signalling-relevant deubiquitinase with pleiotropic, context-dependent functions. This review discusses key knowledge gaps-such as incomplete substrate mapping and determinants of tissue specificity-and outlines translational opportunities and challenges for exploiting JOSD2 as a biomarker and therapeutic target.
Connexin 43 subcellular localization: From trafficking dynamics to pathophysiological outcomes and therapeutic opportunities.
Li H, Luo H, Zhang X … +4 more , Liu R, Li D, Pan Y, Cai Q
Cell Signal · 2026 Sep · PMID 42069098 · Publisher ↗
Connexin 43 (Cx43) exhibits remarkable functional diversity that is precisely dictated by its dynamic subcellular localization. Beyond its canonical role at the plasma membrane, where it assembles into gap junctions (GJs...
Connexin 43 (Cx43) exhibits remarkable functional diversity that is precisely dictated by its dynamic subcellular localization. Beyond its canonical role at the plasma membrane, where it assembles into gap junctions (GJs) and hemichannels (HCs) to mediate intercellular communication, Cx43 translocates to the nucleus and mitochondria, where it exerts non-channel functions including transcriptional regulation and metabolic adaptation. At the plasma membrane, dysregulation of Cx43 trafficking, anchoring, or turnover leads to excessive HC opening and impaired GJ communication, contributing to cardiovascular arrhythmias, ischemia-reperfusion injury, neuroinflammation, osteoporosis, and retinopathy. In the nucleus, Cx43 or its C-terminal fragment enters through importin-dependent pathways, functioning as a non-canonical transcriptional regulator; its mislocalization is implicated in cancer (context-dependent suppression or promotion), hepatic gluconeogenesis in diabetes, and tissue fibrosis. Within mitochondria, Cx43 is imported via Hsp90/TOM complex- or GJA1-20 k-dependent pathways, where it regulates K transport, respiratory chain activity, and redox balance; this mitochondrial pool exerts cardioprotection under preconditioning but exacerbates diabetic cardiomyopathy and neurological injury under pathological stress. This review synthesizes current knowledge on the trafficking mechanisms, pathological outcomes, and therapeutic targeting of Cx43 in these three subcellular compartments. We further discuss peptide-based inhibitors (e.g., Gap19, αCT1), small molecules (e.g., tonabersat, danegaptide), and natural product-derived modulators, highlighting challenges in specificity, bioavailability, and clinical translation. By linking compartment-specific functions to distinct disease entities, this review establishes subcellular localization as a central determinant of Cx43 biology and a promising axis for precision medicine.
Dual regulation of NFS1 by TRIM67-mediated degradation and CEBPA-driven transcription modulates colorectal cancer progression.
Wang B, Huang X, Xing Y … +7 more , Jiao W, Jiang J, Liu G, Li G, Li Q, Yang C, Shi L
Cell Signal · 2026 Sep · PMID 42069097 · Publisher ↗
BACKGROUND: NFS1 cysteine desulfurase (NFS1) a critical enzyme in iron‑sulfur (Fe-S) cluster biogenesis and mitochondrial iron homeostasis, plays a pivotal role in the dysregulation of iron metabolism, a recognized hallm...
BACKGROUND: NFS1 cysteine desulfurase (NFS1) a critical enzyme in iron‑sulfur (Fe-S) cluster biogenesis and mitochondrial iron homeostasis, plays a pivotal role in the dysregulation of iron metabolism, a recognized hallmark of cancer. However, the specific role and regulatory mechanisms of NFS1 in colorectal cancer (CRC) remain poorly understood. This study aimed to elucidate the function of NFS1 in CRC and to uncover the upstream molecular pathways governing its expression. METHODS: The expression of NFS1 in CRC was comprehensively analyzed using public databases (TIMER2.0, TCGA, and TNMplot) and validated in clinical tissue samples and CRC cell lines by quantitative real-time PCR and Western blotting. Loss- and gain-of-function experiments were conducted in SW620 and LoVo cells to assess the effects of NFS1 on cell proliferation, migration, stemness, apoptosis, and ferroptosis, which were evaluated using Cell Counting Kit-8 (CCK-8), EdU, Transwell migration, sphere formation, flow cytometry, and specific metabolic assays. The regulatory mechanisms were investigated through cycloheximide (CHX) chase, ubiquitination, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP) assays. Finally, a xenograft mouse model was established to validate the findings in vivo. RESULTS: NFS1 was significantly upregulated in CRC tissues and cell lines, with its expression associated with tumor-node-metastasis grade, lymph node metastasis, and tumor size. In vitro, NFS1 silencing suppressed CRC cell proliferation, migration, and stemness, while promoting apoptosis and ferroptosis. Mechanistically, tripartite motif containing 67 (TRIM67) directly interacted with NFS1 and promoted its ubiquitination and protein degradation. Conversely, the transcription factor CCAAT/enhancer-binding protein alpha (CEBPA) was found to bind to the NFS1 promoter and positively regulate its transcription. Functional rescue experiments demonstrated that the anti-tumor effects of TRIM67 overexpression or CEBPA silencing were effectively reversed by concurrent NFS1 overexpression. Further, the in vivo xenograft model confirmed that CEBPA knockdown inhibited tumor growth and tumor lung metastasis by downregulating NFS1. CONCLUSION: In CRC, the oncogenic transcription factor CEBPA positively regulated NFS1 transcription, while the E3 ligase TRIM67 promoted its ubiquitination and degradation. Both TRIM67 overexpression and CEBPA silencing suppressed the malignant progression of CRC by downregulating NFS1, highlighting the TRIM67/CEBPA/NFS1 axis as a potential therapeutic target.
β-Hydroxybutyrate prevents bone loss partially via the histone β-hydroxybutyrylation pathway.
He Y, Mou C, Tang M … +16 more , Luo L, Zhou T, Cheng X, Li D, Luo C, Guo M, Hu J, Li Q, Wan Q, Deng L, Li Y, Zhang H, Ni Q, Xu Y, Gao C, Huang W
Cell Signal · 2026 Sep · PMID 42069096 · Publisher ↗
Osteoporosis (OP) is a systemic metabolic bone disorder. The excessive activation of osteoclasts (OCs) leads to a decrease in bone mass and damage to the bone microstructure, which plays a crucial role in OP. β-Hydroxybu...
Osteoporosis (OP) is a systemic metabolic bone disorder. The excessive activation of osteoclasts (OCs) leads to a decrease in bone mass and damage to the bone microstructure, which plays a crucial role in OP. β-Hydroxybutyrate (BHB), the main component of ketone bodies, not only serves as an ancillary fuel substituting for glucose but also induces anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone β-hydroxybutyrylation (Kbhb). Recent research has found that BHB has a positive therapeutic effect on OP, but the underlying molecular mechanism remains unclear. In this study, we established OP animal models induced by estrogen deficiency and type 2 diabetes using ovariectomized (OVX) and db/db mice, respectively, and administered BHB to OP mice via free drinking in vivo. Our results indicated that BHB increased bone mineral density (BMD), improved bone microstructure, and inhibited OC formation. Additionally, BHB upregulated the levels of PanKbhb, H3K9bhb, and H3K27bhb modifications in the bone tissue of OP mice. In vitro, we found that BHB or β-hydroxybutyryl-CoA (BHB-CoA) could inhibit RANKL-induced OC differentiation and bone resorption, and upregulate histone Kbhb levels in a concentration-dependent manner. Furthermore, the effects of BHB or BHB-CoA-induced histone Kbhb were reversed by inhibiting the activity of acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300. In summary, our data reveal that BHB may alleviate bone loss caused by estrogen deficiency and type 2 diabetes through ACSS2/P300-induced histone Kbhb.
The CAMK protein family: Pivotal roles in calcium-dependent disease pathways and emerging therapeutic strategies.
Fu R, Wang Y, Wang W … +3 more , Song Q, Zhang H, Yang L
Cell Signal · 2026 Aug · PMID 42066831 · Publisher ↗
Calmodulin (CAM) is a highly conserved calcium ion sensor in eukaryotic cells. Its molecule contains four EF-hand domains, which can respond to changes in intracellular calcium ion concentration and conduct signals. As t...
Calmodulin (CAM) is a highly conserved calcium ion sensor in eukaryotic cells. Its molecule contains four EF-hand domains, which can respond to changes in intracellular calcium ion concentration and conduct signals. As the core mediator of calcium signals, CAM further activates the downstream Calcium/calmodulin-dependent protein kinases (CAMK) family. CAMK is a type of serine/threonine protein kinase with catalytic and regulatory domains. Its classical activation method is the formation of a complex between intracellular calcium ions and CAM and binding to the regulatory domain of CAMK, inducing conformational changes, thereby phosphorylating downstream effect proteins. Besides calcium ions, its activity can also be regulated by small molecules such as citric acid. In the field of oncology, CAMK2 is overexpressed in various malignant tumors such as non-small cell lung cancer and colorectal cancer, and is closely related to tumor proliferation, invasion, and poor prognosis. The mechanism involves regulating tumor stem cells and AMPK and other signaling pathways. In addition, the CAMK family also participates in inflammatory responses by regulating NF-κB and intervenes in metabolic processes such as glycolysis and fatty acid β-oxidation, thereby playing a role in immune diseases and metabolic disorders. In summary, the CAMK family serves as a key hub of calcium signals and is widely involved in the processes of cardiovascular diseases, tumors, immune abnormalities, and metabolic disorders. In-depth exploration of its structure and regulatory mechanisms will provide new targets and strategies for the treatment of related diseases.
NSUN5-CBX8 mC axis promotes gastric tumorigenesis by activating JAK-STAT3 signaling.
Yin J, Li L, Niu Y … +5 more , Wang Q, Liu W, Gu Y, Wang X, Huang L
Cell Signal · 2026 Sep · PMID 42066830 · Publisher ↗
Emerging evidence implicates dysregulated RNA methylation in tumorigenesis across cancers. Among RNA methyltransferases, NSUN5 exhibits the highest alteration frequency in gastric cancer (GC), yet its functional and mech...
Emerging evidence implicates dysregulated RNA methylation in tumorigenesis across cancers. Among RNA methyltransferases, NSUN5 exhibits the highest alteration frequency in gastric cancer (GC), yet its functional and mechanistic contributions remain largely elusive. In this study, we report that Nsun5 gene depletion significantly suppressed gastric tumorigenesis in Trp53; Kras; Villin-Cre model mice. Wild-type Nsun5, but not its catalytically inactive mutant Nsun5, largely rescued tumor formation in Nsun5-depleted Trp53; Kras cells. Mechanistically, NSUN5 increases chromobox 8 (CBX8) protein levels by methylating and stabilizing CBX8 mRNA. As a core component of polycomb repressive complex 1 (PRC1), increased CBX8 protein expression leads to increased inhibition of the expression of SOCS2 and ultimately activates the JAK-STAT3 signaling pathway. Furthermore, the CBX8 inhibitor SW2-110A effectively antagonized Nsun5-triggered tumor formation by Trp53; Kras GC cells. Collectively, our findings revealed how NSUN5 drives GC and revealed a promising lead compound that inhibits GC tumorigenesis.
LC3B promotes bladder cancer cell proliferation via the Sp1-cyclin D1/p27 axis with pan-cancer clinical associations.
Zhang Y, Zhao K, Du W … +9 more , Hu L, Jin Z, Chen L, Pan X, Lan X, Chu Z, Qian X, Jin H, Huang C
Cell Signal · 2026 Sep · PMID 42066829 · Publisher ↗
Microtubule-associated protein 1 light chain 3 beta (MAP1LC3B, LC3B) is a core autophagy-related protein, yet its functional role in bladder cancer remains incompletely understood. In this study, we aimed to clarify the...
Microtubule-associated protein 1 light chain 3 beta (MAP1LC3B, LC3B) is a core autophagy-related protein, yet its functional role in bladder cancer remains incompletely understood. In this study, we aimed to clarify the expression pattern, biological function, and molecular mechanism of LC3B in bladder cancer and to further assess its broader clinical relevance across human cancers. Single-cell RNA sequencing revealed that LC3B is predominantly expressed in bladder cancer epithelial cells and is closely associated with cell cycle-related pathways. Functional studies in T24T and J82 bladder cancer cells revealed that LC3B knockout markedly suppressed tumor cell proliferation both in vitro and in vivo. Mechanistically, LC3B promoted G1/S phase transition by enhancing Sp1-mediated Cyclin D1 transcription while repressing p27 expression, thereby driving bladder cancer cell proliferation. Additional pan-cancer analyses showed that LC3B is aberrantly expressed across multiple tumor types and is significantly associated with tumor stage, genomic instability, and patient prognosis. Gene set enrichment analyses further suggested that LC3B may participate in transcriptional and metabolic reprogramming, supporting a noncanonical function that appears to be independent of LC3B lipidation. Collectively, these findings identify LC3B as a critical regulator of bladder cancer cell proliferation through the Sp1-Cyclin D1/p27 axis and provide new insight into its potential clinical relevance in bladder cancer and other malignancies.
FOXP4-AS1 suppresses papillary thyroid carcinoma progression by binding to Lactate Dehydrogenase A and suppressing its expression, with implications for metabolic-targeted therapy.
Ma N, Tian HY, Zhao W … +4 more , Peng H, Zeng S, Zhao DW, Yu ZY
Cell Signal · 2026 Sep · PMID 42066828 · Publisher ↗
Although FOXP4-AS1 exerts oncogenic effects in multiple cancers, this study reveals that it suppresses PTC progression. A series of experiments demonstrate that overexpression of FOXP4-AS1 inhibits PTC cell proliferation...
Although FOXP4-AS1 exerts oncogenic effects in multiple cancers, this study reveals that it suppresses PTC progression. A series of experiments demonstrate that overexpression of FOXP4-AS1 inhibits PTC cell proliferation, migration, and invasion, whereas its knockdown promotes these malignant phenotypes and enhances tumorigenesis in nude mice. FOXP4-AS1 is distributed in both the nucleus and cytoplasm, enriched in the aerobic glycolysis pathway, and binds to Lactate Dehydrogenase A (LDHA)-a key enzyme in aerobic glycolysis with known links to tumor metabolic microenvironment. LDHA was primarily localized in the cytoplasm, and its downregulation suppressed the malignant behavior of PTC cells. Further mechanistic investigations reveal that knockdown of FOXP4-AS1 increases LDHA expression, and additional inhibition of LDHA partially reverses the pro-tumor effects induced by FOXP4-AS1 silencing. In conclusion, this study identifies FOXP4-AS1 as a tumor suppressor in PTC and elucidates the regulatory mechanism of the FOXP4-AS1/LDHA axis by which FOXP4-AS1 represses LDHA expression to attenuate aerobic glycolysis, providing novel insights into the mechanisms of PTC progression and potential therapeutic targets and diagnostic biomarkers relevant to metabolic modulation in PTC.
The dual role of kindlin-2 in mechanotransduction: A bridge for sensing and a hub for signaling.
Li Y, Liu B, Shao S
Cell Signal · 2026 Sep · PMID 42066827 · Publisher ↗
The bidirectional communication between the cell and the extracellular mechanical microenvironment established by integrins and various adhesion proteins is a well-established paradigm of mechanotransduction. Kindlin-2,...
The bidirectional communication between the cell and the extracellular mechanical microenvironment established by integrins and various adhesion proteins is a well-established paradigm of mechanotransduction. Kindlin-2, belonging to the 4.1-ezrin-ridixin-moesin (FERM) domain family of proteins, has emerged as a key mechanosensitive protein. Here, we start with the unique structure of kindlin-2, then review the performance of kindlin-2 in mechanotransduction by focusing on its two potential modes of function: as a physical structure for mechanosensing and as a member of multiple pathways for mechanosignaling. Finally, we discuss the relationship between kindlin-2 and pathological states associated with an aberrant mechanical microenvironment. We hope the discussions around kindlin-2 can establish a theoretical framework for regarding kindlin-2 as a mechanomedicine target in future therapeutic research.
Corrigendum to "VDAC1-mediated cytosolic leakage of mtDNA triggers pyroptosis of nucleus pulposus cells by activating the TLR9 signaling pathway" [Cellular Signaling 142 (2026) 112387].
Hu T, Yan M, Chen Y … +5 more , Chen S, Song Z, Jing X, Hu B, Liu H
Cell Signal · 2026 Aug · PMID 42055923 · Publisher ↗
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Nobiletin reprograms cancer cell fate signaling: PI3K/Akt/mTOR-MAPK crosstalk, NF-kB/STAT3 inhibition and chemosensitization.
Kamath AJ, Syam S, Rajesh G … +7 more , Renjini S, Vinod BS, Raj DBSA, Nath LR, Sharifi-Rad J, Setzer WN, Calina D
Cell Signal · 2026 Aug · PMID 42049080 · Publisher ↗
Nobiletin, a polymethoxylated flavonoid derived from citrus peels, exhibits a wide range of anticancer activities, including inhibition of proliferation, induction of apoptosis, suppression of angiogenesis, modulation of...
Nobiletin, a polymethoxylated flavonoid derived from citrus peels, exhibits a wide range of anticancer activities, including inhibition of proliferation, induction of apoptosis, suppression of angiogenesis, modulation of autophagy, and arrest of cell cycle progression. These effects are mediated through the regulation of multiple oncogenic and survival signaling pathways, such as PI3K/Akt/mTOR, MAPK, NF-κB, and STAT3. Despite its potent preclinical efficacy, the clinical translation of nobiletin remains limited by poor aqueous solubility, minimal oral bioavailability, and rapid metabolism. This review synthesizes in vitro, in vivo, and pharmacokinetic data to elucidate the mechanistic basis of nobiletin's anticancer activity and summarizes emerging formulation strategies designed to enhance its pharmacokinetic profile. Literature searches across major databases identified studies investigating its molecular targets, delivery systems, and therapeutic outcomes. Nobiletin consistently suppressed tumor growth across diverse cancer models, with synergistic effects observed in combination with chemotherapeutics. Advanced delivery approaches, including nanoparticles, self-microemulsifying drug delivery systems, plant exine capsules, and transdermal enhancers, markedly improved solubility, stability, and systemic exposure in preclinical studies. However, translational gaps remain, with no completed clinical trials in oncology and limited human pharmacokinetic data. Current evidence positions nobiletin as a promising multi-target anticancer agent with potential to overcome drug resistance and enhance existing therapies. Future research should prioritize optimizing bioavailability, assessing metabolite activity, and conducting rigorously designed clinical trials to establish its safety and efficacy in cancer patients.
Importin α as a central regulator of nucleocytoplasmic transport: Structural basis, isoform diversification, and disease implications.
Liu Y, Wang Z, Wei S … +4 more , Yang H, Ren M, Fu X, Chen Z
Cell Signal · 2026 Aug · PMID 42044761 · Publisher ↗
Eukaryotic cellular homeostasis and function rely on efficient and specific nucleocytoplasmic transport, mediated by nuclear transport machinery. Importin α (Impα), a central adaptor protein in the classical nuclear impo...
Eukaryotic cellular homeostasis and function rely on efficient and specific nucleocytoplasmic transport, mediated by nuclear transport machinery. Importin α (Impα), a central adaptor protein in the classical nuclear import pathway, recognizes cargo proteins containing nuclear localization signals (NLSs) and facilitates their translocation into the nucleus. Structurally, this process involves interaction between the importin-β-binding (IBB) domain of Impα and importin β (Impβ), as well as recognition of cargo NLS motifs by major and minor NLS-binding sites formed by armadillo (ARM) repeat domains. The nuclear import function of Impα depends on coordinated spatial configuration and interactions among these conserved structural elements. Comparative structural analyses of Impα from representative organisms-including humans, mice, plants, and fungi-reveal conserved core functional modules with lineage-specific structural variations supporting functional adaptation across taxa. From a pathological perspective, Impα is implicated in multiple human diseases, with dysregulation often rooted in structural and molecular mechanisms. Many viruses exploit the conserved NLS recognition domain of Impα by encoding proteins that mimic host NLSs, hijacking the classical nuclear import pathway to enable viral nuclear entry and immune evasion. In cancer and other chronic diseases, aberrant expression or structural-functional impairment of Impα disrupts nucleocytoplasmic distribution of key signaling molecules and transcriptional regulators, driving disease progression. Given its structural characteristics and role in disease, Impα has emerged as a promising therapeutic target. A systematic understanding of Impα from structure to function and disease relevance provides a framework for developing therapeutic strategies to modulate nucleocytoplasmic transport pathways.
Corrigendum to "Study on the molecular mechanism of KPNA2 regulation of myocardial ischemia/delayed reperfusion injury through mitophagy" [Cellular Signalling 136 (2025) 112157].
Tao E, Tao Z, Wang F … +6 more , Bai S, Lai S, Li X, Bai Y, Peng C, Wan L
Cell Signal · 2026 Aug · PMID 42036252 · Publisher ↗
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Realgar Transforming Solution (RTS)-induced lysosomal pH perturbation activates a non-canonical Ca²⁺-associated mitochondrial apoptotic pathway in TNBC cells.
Wang R, Li Z, Yue Z … +7 more , Uddin S, Zhang W, Zhao Q, Chen J, Wang X, Li Y, Li H
Cell Signal · 2026 Aug · PMID 42036001 · Publisher ↗
Dysregulation of intracellular Ca signaling is a critical determinant of cell fate; however the contribution of non-canonical Ca reservoirs to cancer-selective apoptosis remains incompletely understood. In this study, re...
Dysregulation of intracellular Ca signaling is a critical determinant of cell fate; however the contribution of non-canonical Ca reservoirs to cancer-selective apoptosis remains incompletely understood. In this study, realgar transforming solution (RTS), a microbially processed arsenical, was employed as a biologically informative perturbation to investigate the potential link between lysosomal pH dysregulation and a Ca-associated mitochondrial apoptotic program in triple-negative breast cancer (TNBC) cells. RTS displayed selective inhibitory activity compared with inorganic arsenic trioxide (ATO) and paclitaxel, leading to reduced viability of TNBC cells (MDA-MB-231, BT-549, and MDA-MB-468) while showing minimal impact on non-malignant MCF-10 A cells. RTS-induced cell death was linked to a Ca-mediated mitochondrial program-marked by cytochrome c release and caspase-9 activation-while showing limited correlation with reactive oxygen species (ROS) accumulation or p53 signaling. Mechanistically, RTS triggered sustained cytosolic and mitochondrial Ca overload derived primarily from lysosomal mobilization rather than extracellular influx or endoplasmic reticulum depletion. Time-course profiling observed lysosomal acidic intensification as an early event, preceding TRPML1-mediated Ca efflux and subsequent lysosomal membrane permeabilization (LMP). Consistently, pharmacological neutralization of the acidic shift (BafA1) or TRPML1 inhibition (ML-SI1) significantly attenuated the cytosolic Ca elevation observed at the measured intervals. Collectively, these in vitro findings highlight a potential"lysosome-mitochondria" signaling axis in which early pH perturbation may represent a vulnerability in TNBC. While the multicomponent nature of RTS requires further characterization, this study provides preliminary insights into targeting organelle-specific Ca hubs as a possible complementary strategy for refractory solid tumors.
IL-33/ST2 axis delays disc degeneration through PI3K/AKT-dependent regulation of nucleus pulposus cell proliferation and apoptosis.
Wang H, Zhou P, Chen Y … +2 more , Li Y, Liu J
Cell Signal · 2026 Aug · PMID 42025895 · Publisher ↗
OBJECTIVE: To investigate the proliferation and apoptosis of nucleus pulposus cells stimulated by IL-33, as well as the activation of the PI3K/AKT signaling pathway in these cells, and to determine whether this pathway i...
OBJECTIVE: To investigate the proliferation and apoptosis of nucleus pulposus cells stimulated by IL-33, as well as the activation of the PI3K/AKT signaling pathway in these cells, and to determine whether this pathway is regulated by the IL-33/ST2 axis. METHODS: Wild-type mice, IL-33 knockout (KO) mice, and ST2 KO mice were used to establish a model of intervertebral disc degeneration in the tail vertebrae. HE staining and Masson staining were employed to assess the degree of disc degeneration in the modeled regions. Immunofluorescence was conducted to verify the localization of IL-33 and Collagen-II, while ELISA was used to measure the expression levels of Collagen-II in the modeled areas. An in vitro model of nucleus pulposus cells was established, with IL-33 administered in a time and concentration gradient. Western blotting was used to detect changes in the expression of Collagen-II, Aggrecan, P-PI3K, and P-AKT. Additionally, flow cytometry was utilized to assess the cell cycle and apoptosis of the nucleus pulposus cells in each group, and CCK-8 assays were performed to evaluate the proliferation of cells in each group. RESULT: In the intervertebral disc degeneration group, the expression of IL-33 in the modeling area of mice was found to be downregulated. Furthermore, the degree of intervertebral disc degeneration in IL-33 and ST2 knockout mice was exacerbated compared to wild-type mice. With the extension of IL-33 stimulation time and the intensification of the effect, the proliferation activity of nucleus pulposus cells increased, while the degree of apoptosis decreased. Additionally, IL-33 was able to activate the PI3K/AKT signaling pathway in nucleus pulposus cells, and this biological activity could be inhibited by Anti-ST2. CONCLUSION: In conclusion, IL-33 can activate the PI3K/AKT signaling pathway in nucleus pulposus cells, promoting their proliferation and inhibiting apoptosis, and this biological activity is regulated by the IL-33/ST2 axis.
Reactivating mitochondrial quality control via the Nrf2 pathway to combat metabolic stress in diabetic osteoarthritis.
Chen Y, Xiao J, Yu Y … +1 more , Si HB
Cell Signal · 2026 Aug · PMID 42025894 · Publisher ↗
The intersection of diabetes mellitus (DM) and osteoarthritis (OA) defines a distinct metabolic phenotype, commonly termed diabetic osteoarthritis (DOA), in which systemic metabolic toxicity independently accelerates art...
The intersection of diabetes mellitus (DM) and osteoarthritis (OA) defines a distinct metabolic phenotype, commonly termed diabetic osteoarthritis (DOA), in which systemic metabolic toxicity independently accelerates articular degeneration. In addition to shared risk factors, this review delineates the molecular framework of DOA, detailing how persistent hyperglycemia initiates oxidative stress, chronic inflammation, and the accumulation of advanced glycation end products (AGEs), disrupting chondrocyte bioenergetic homeostasis. A pivotal event in this process is the dysregulation of mitochondrial quality control (MQC), a central regulatory mechanism that maintains cellular viability under metabolic stress. We further emphasize the dysregulation of the Nrf2 signaling pathway as a critical upstream determinant of mitochondrial dysfunction. By integrating epidemiological findings with mechanistic evidence, we propose that therapeutic restoration of the Nrf2-MQC axis may offer a rational strategy to preserve mitochondrial integrity and slow the progression of diabetes-associated joint degeneration.
PHC2 promotes hepatocellular carcinoma progression and serves as a robust prognostic biomarker: A pancancer multiomics and clinical validation study.
Wang Q, Ye Y, Qin S … +3 more , Luo M, Yang J, Zhang M
Cell Signal · 2026 Aug · PMID 42025893 · Publisher ↗
PURPOSE: Polyhomeotic homolog 2 (PHC2) is a key component of Polycomb repressive complex 1, yet its clinical significance and biological function in hepatocellular carcinoma (HCC) remain unclear. This study aimed to eluc...
PURPOSE: Polyhomeotic homolog 2 (PHC2) is a key component of Polycomb repressive complex 1, yet its clinical significance and biological function in hepatocellular carcinoma (HCC) remain unclear. This study aimed to elucidate the expression patterns, prognostic value, and oncogenic role of PHC2 in HCC progression. METHODS: Multiomics datasets (e.g., TCGA, GTEx, and scRNA-seq) were analyzed to evaluate PHC2 expression and its correlation with the tumor microenvironment. Clinical validation was performed via immunohistochemistry using a tissue microarray (TMA) containing 94 HCC patient samples. The biological functions of PHC2 were investigated through in vitro assays (e.g., colony formation, wound healing, and Transwell) in HCC cell lines and an in vivo subcutaneous xenograft model. RESULTS: Pancancer analysis revealed that PHC2 was significantly upregulated in HCC and correlated with poor prognoses across multiple malignancies, including brain lower grade glioma and adrenocortical carcinoma. Bioinformatic analyses suggested a potential correlation between PHC2 and macrophage infiltration. In the clinical TMA cohort, elevated PHC2 protein expression was significantly associated with advanced pathological stage and was identified as a robust independent risk factor for poor overall survival. Functionally, PHC2 knockdown markedly inhibited HCC cell proliferation, migration, and invasion in vitro. Conversely, PHC2 overexpression accelerated tumor growth in vivo, accompanied by the upregulation of proliferation markers Ki-67 and PCNA. CONCLUSIONS: Our study identified PHC2 as a novel oncogenic driver that contributes to HCC progression and serves as a powerful independent prognostic biomarker. These findings highlight PHC2 as a promising therapeutic target, warranting further investigation into its dual role in tumor growth and microenvironment remodeling.
Clec7a promotes hippocampal microglial activation in rats with status epilepticus via inducing the TLR4/MyD88/NF-κB signaling pathway.
Dai F, Chen YH
Cell Signal · 2026 Aug · PMID 42025892 · Publisher ↗
Microglial polarization imbalance between pro-inflammatory M1 and anti-inflammatory M2 phenotypes is a key mechanism in epilepsy-related neuroinflammation. This study explores the role of C-type lectin domain containing...
Microglial polarization imbalance between pro-inflammatory M1 and anti-inflammatory M2 phenotypes is a key mechanism in epilepsy-related neuroinflammation. This study explores the role of C-type lectin domain containing 7A (Clec7a) in M1 microglial polarization in epilepsy. An AAV-shClec7a was injected intra-hippocampally into Sprague-Dawley rats prior to induction of status epilepticus (SE) using lithium-pilocarpine. CLEC7A expression was assessed via qRT-PCR and Western blot. Histopathology was evaluated using H&E and Nissl staining. M1 markers and cytokines were analyzed by qRT-PCR/Western blot. The effects of Clec7a silencing were examined in kainic acid-stimulated BV2 cells and primary microglia. CLEC7A was significantly upregulated in epileptic models. AAV-shClec7a reduced Racine score, seizure frequency and duration, alleviated hippocampal damage, and suppressed M1 polarization and neuroinflammation, evidenced by decreased IBA1, iNOS, IL-1β, IL-6, and TNF-α, and increased IL-10 levels. Silencing Clec7a in vitro also inhibited M1 polarization and inflammation, and suppressed TLR4/MyD88/NF-κB pathway activation. Overexpression of Nfkb reversed the inhibition of M1 polarization induced by Clec7a silencing. Meanwhile, TLR4 inhibitor TAK-242 reversed Clec7a-induced M1 polarization. Clec7a is upregulated in epilepsy and promotes M1 polarization and neuroinflammation, mediated at least partially through the TLR4/MyD88/NF-κB signaling pathway.
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