Cell. Signal. [JOURNAL]
Sun
200 papers
Targeting lipoprotein lipase-positive macrophage-driven GDF-15 expression alleviates cancer Cachexia in obese head and neck squamous cell carcinoma.
Guo YJ, Zhao R, Li YH … +6 more , Cui JJ, Zhao MR, Yang Y, Wu JY, Zao JH, Song X
Cell Signal · 2026 Jul · PMID 42401358 · Publisher ↗
Head and neck squamous cell carcinoma (HNSCC) is often associated with dysphagia and malnutrition, predisposing patients to cancer cachexia, which adversely affects postoperative prognosis and survival. Obese patients ma...
Head and neck squamous cell carcinoma (HNSCC) is often associated with dysphagia and malnutrition, predisposing patients to cancer cachexia, which adversely affects postoperative prognosis and survival. Obese patients may exhibit underlying muscle wasting, a condition related to sarcopenic obesity, even when early body-weight loss is not prominent. Here, we identified a lipoprotein lipase-positive (LPL-positive) macrophage population in HNSCC that increased during tumor progression and was enriched in tumors from overweight/obese patients and high-fat diet-fed tumor-bearing mice. A high LPL-positive macrophage signature score based on TCGA-HNSC bulk transcriptomic and clinical follow-up data was associated with worse overall survival. LPL-positive macrophage-associated lipid metabolic changes were accompanied by increased growth differentiation factor 15 (GDF-15) secretion. Conditioned medium from LPL-overexpressing RAW264.7 macrophages and recombinant GDF-15 induced myotube atrophy and ferroptosis-related lipid peroxidation, whereas liproxstatin-1 or ferrostatin-1 partially reversed these effects. Systemic pharmacological lipase/LPL inhibition with Poloxamer 407 (P-407) or orlistat reduced LPL enzymatic activity, although these treatments also affected systemic lipid metabolism. Invalidation of LPL by siRNA in RAW264.7 cells further showed reduced GDF-15 secretion and attenuated conditioned-medium-induced myotube atrophy. These findings suggest that macrophage-associated LPL activity and GDF-15 contribute to muscle wasting in obese HNSCC and highlight a potential metabolic-immunologic axis involved in cancer cachexia. Using animal models, we further showed that systemic pharmacological lipase/LPL inhibition with P-407, particularly when combined with anti-PD-1 therapy, attenuated muscle wasting and improved the tumor immune microenvironment.
BRD8 promotes non-small cell lung cancer progression by stabilizing MBD2 and activating the MAPK pathway.
Dong L, Zhou Y, Cui Q … +4 more , Chen Z, Wang T, Wu D, Lin X
Cell Signal · 2026 Jul · PMID 42401357 · Publisher ↗
Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cases with limited therapeutic options and poor clinical outcomes....
Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cases with limited therapeutic options and poor clinical outcomes. Bromodomain-containing protein 8 (BRD8), an epigenetic regulator, has been reported to exert oncogenic roles in multiple solid tumors. Nevertheless, its biological functions and molecular mechanisms in NSCLC remain largely uncharacterized, which motivates us to explore its role in NSCLC progression. The mitogen-activated protein kinase (MAPK) pathway is a well-recognized core oncogenic cascade driving NSCLC malignant phenotypes. Our transcriptome profiling further revealed that the MAPK pathway was the most significantly enriched signaling pathway downstream of BRD (Bromodomain-containing protein), thus we selected it as the key pathway for in-depth mechanistic investigation. In the present study, we found that BRD8 (Bromodomain-containing protein8) was markedly overexpressed in clinical NSCLC tissues and cell lines. Functional assays demonstrated that BRD8 prominently promoted the proliferation, migration and invasion of NSCLC cells. Co-immunoprecipitation combined with mass spectrometry confirmed the direct interaction between BRD8 and MBD2 (methyl-CpG-binding domain protein 2), and their binding was located at the methyl-CpG-binding domain of MBD2. Ubiquitination assays showed that BRD8 enhanced the total and K63 (Lysine63)-linked polyubiquitin chains of MBD2. As a typical post-translational modification, K63-linked ubiquitination generally does not trigger proteasomal degradation but maintains protein stability. Cycloheximide chase assays verified that BRD8 prolonged the half-life of MBD2 and enhanced its stability. Subsequent rescue experiments using the MBD2 K63 mutant demonstrated that mutation at this lysine residue of MBD2 abolishes BRD8-mediated assembly of K63-linked polyubiquitin chains and impairs MBD2 stability. Mechanically, MBD2 acted as a critical downstream effector to mediate BRD8-induced activation of the MAPK pathway. In vivo nude mouse xenograft experiments indicated that knockdown of BRD8 or MBD2 dramatically suppressed tumor growth and decreased MAPK pathway activity. In conclusion, BRD8 facilitates NSCLC progression by interacting with MBD2 to enhance its K63-linked ubiquitination and protein stability, thereby activating the MAPK signaling pathway. This preclinical investigation elucidates the BRD8/MBD2 oncogenic mechanism and provides evidence for subsequent NSCLC research.
Hypoxia remodels circSTX6 nuclear export through URH49-ALYREF to drive IGF1-mediated bladder cancer progression.
Chen Y, Zhuang J, Yu H … +11 more , Li K, Zhang Y, Sun H, Jiang L, Yang Z, Bai K, Tao Y, Feng T, Yang H, Yang X, Lu Q
Cell Signal · 2026 Jul · PMID 42401356 · Publisher ↗
BACKGROUND: Although circRNAs are increasingly implicated in tumor biology, most studies emphasize expression changes while overlooking subcellular distribution. The mechanisms governing circRNA nuclear export in bladder...
BACKGROUND: Although circRNAs are increasingly implicated in tumor biology, most studies emphasize expression changes while overlooking subcellular distribution. The mechanisms governing circRNA nuclear export in bladder cancer (BCa) and their contribution to progression are poorly defined. METHODS: Differential expressed circRNAs between BCa and adjacent tissues were identified through bioinformatic analysis. Oncologic phenotypes were assessed using CCK-8, colony-formation, transwell, EdU assays in vitro, and subcutaneous xenograft and tail-vein lung metastasis mouse models in vivo. The circSTX6 interactome and transcript-level effects were characterized by RNA-seq, RNA immunoprecipitation (RIP), RNA pull-down, and mass spectrometry. Hypoxia treatment, nuclear-cytoplasmic fractionation, and FISH were used to quantify circSTX6 subcellular localization and oxygen-dependent dynamics. RESULTS: circSTX6 was upregulated in BCa tissues and cells and promoted malignant phenotypes both in vitro and in vivo. Hypoxia increased circSTX6 nuclear retention. Mechanistically, hypoxia induced KCMF1-mediated ubiquitination and degradation of URH49 while upregulating ALYREF, thereby impairing URH49-dependent circSTX6 nuclear export and further promoting circSTX6 nuclear retention. Nuclear-retained circSTX6 bound HNRNPA2B1 and stabilized IGF1 mRNA, activating a circSTX6/HNRNPA2B1/IGF1 axis that enhanced BCa proliferation and migration. CONCLUSION: Hypoxia remodels circSTX6 nuclear export through URH49 degradation and ALYREF upregulation, resulting in circSTX6 nuclear retention and enhanced IGF1-mediated BCa progression.
Integrative spatiotemporal analysis uncovers an Fto-mediated epigenetic-metabolic axis governing myocardial ischemic injury.
Chen R, Wang X, Wang R … +11 more , Zhang Z, Qin L, Liu Z, Lan H, Wu J, Liu S, Chen Z, Luan X, Li B, Li G, Chu X
Cell Signal · 2026 Jul · PMID 42392289 · Publisher ↗
Fat mass and obesity-associated protein (Fto), a pivotal RNA N-methyladenosine (mA) demethylase, is critically involved in the progression of myocardial infarction (MI). However, the role of Fto in MI remains controversi...
Fat mass and obesity-associated protein (Fto), a pivotal RNA N-methyladenosine (mA) demethylase, is critically involved in the progression of myocardial infarction (MI). However, the role of Fto in MI remains controversial; divergent observation timeframes and unclarified cell-type specificity hinder consensus on its post-MI expression profile and biological functions. In this study, by integrating transcriptomic and single-nucleus sequencing data, we revealed that post-MI Fto downregulation predominantly targets cardiomyocytes and facilitates their apoptosis in an mA-dependent manner. In vitro, Fto knockdown promoted mA levels, impaired mitochondrial ATP synthesis, and drove oxidative stress and apoptosis. Overexpression of Fto rescued OGD-induced mitochondrial dysfunction and apoptosis. Interestingly, the mA inhibitor cycloleucine reversed Fto deficiency-induced mitochondrial dysfunction, confirming that Fto regulates cardiac metabolism and apoptosis in an mA-dependent manner. In vivo, AAV9-mediated cardiac-specific overexpression of Fto protected against MI injury by improving cardiac function and attenuating fibrosis and apoptosis. In conclusion, this study constructed the first single-cell spatiotemporal expression map of Fto after myocardial infarction, resolving previous contradictory findings regarding Fto's biological function. We demonstrated that Fto deficiency aggravates ischemic injury via mA-mediated mitochondrial dysfunction and apoptosis, identifying Fto as a viable clinical target for MI.
Caspase-3 activation is a brake in GSDMD-mediated pyroptosis.
Li G, Peng M, Li M … +12 more , Hu R, Gao C, Xing Y, Zhang T, Xu J, Fu M, Liang W, Feng P, Zhang H, Zhang Z, Zheng P, Chu X
Cell Signal · 2026 Jul · PMID 42392288 · Publisher ↗
Pyroptosis is a form of programmed cell death mediated by gasdermin proteins, with GSDMD and GSDME being the most extensively studied. Inflammatory caspases-1 or caspases-4/5/11 cleave GSDMD and release its pore-forming...
Pyroptosis is a form of programmed cell death mediated by gasdermin proteins, with GSDMD and GSDME being the most extensively studied. Inflammatory caspases-1 or caspases-4/5/11 cleave GSDMD and release its pore-forming fragment GSDMD-NT, whereas the apoptotic caspase-3, cleaves GSDME and releases its pore-forming fragment GSDME-NT. In this study, we observed that caspase-3 is activated during GSDMD-mediated pyroptosis. Interestingly, downregulation of caspase-3 activity either through RNAi or caspase-3 inhibitor significantly increased cell death. Furthermore, we found that caspase-3 physically interacts with GSDMD-NT and cleaves it at a site distinct from those targeted by caspase-1 or caspases-4/5/11. This alternative cleavage generates a non-functional fragment of GSDMD-NT, thereby disrupting its integrity. Consequently, we demonstrate that caspase-3 activation serves as a negative feedback mechanism to regulate the intensity of GSDMD-NT-mediated pyroptosis.
ILF3 promotes proliferation and invasion of hepatocellular carcinoma cells through STAT3 phosphorylation and formation of an endogenous complex with SRPK1.
Yu J, Yang Y, Guo Z … +3 more , Chen Y, Lei S, Deng X
Cell Signal · 2026 Jul · PMID 42392287 · Publisher ↗
Interleukin enhancer-binding factor 3 (ILF3/NF90) is a multifunctional nuclear factor implicated in diverse malignancies, yet whether ILF3 engages functionally relevant protein-protein interactions within hepatocellular...
Interleukin enhancer-binding factor 3 (ILF3/NF90) is a multifunctional nuclear factor implicated in diverse malignancies, yet whether ILF3 engages functionally relevant protein-protein interactions within hepatocellular carcinoma (HCC) signaling networks remains incompletely defined. Here, we show that ILF3 is upregulated in HCC across public cohorts and local tissue specimens and that higher ILF3 abundance is associated with adverse clinical features. ILF3 depletion suppresses HCC cell proliferation, migration, invasion, and xenograft growth. Unbiased immunoprecipitation-mass spectrometry identifies serine/arginine-rich protein-specific kinase 1 (SRPK1) as an endogenous interaction partner of ILF3. ILF3 knockdown reduces SRPK1 abundance by accelerating SRPK1 mRNA decay, whereas SRPK1 reconstitution restores STAT3 phosphorylation and substantially rescues the impaired malignant phenotypes. Conversely, SRPK1 knockdown phenocopies ILF3 depletion and reduces p-STAT3 (Tyr705) without materially altering total STAT3. RNA-seq and qPCR validation show coordinated disruption of JAK-STAT-related transcriptional programs after ILF3 loss, and tissue immunohistochemistry supports reduced ILF3, SRPK1, p-STAT3 (Tyr705), Bcl-2, and Ki67 in ILF3-depleted xenografts. These findings establish a functional ILF3-SRPK1-STAT3 relationship in HCC and indicate that ILF3 supports malignant progression partly by maintaining SRPK1 abundance and STAT3 signaling competence.
Extracellular regucalcin blocks the proliferation and metastatic activity of SK-N-SH human neuroblastoma cells by targeting diverse signaling pathways: Involvement in the cancer cell microenvironment.
Yamaguchi M, Jijiwa M, Shimokawa N … +2 more , Murata T, Ghanem NZ
Cell Signal · 2026 Jul · PMID 42385924 · Publisher ↗
Regucalcin plays an inhibitory role in various cell signaling systems, including calcium signaling. Recent studies have demonstrated its role as a cancer-suppressing protein. Notably, extracellular regucalcin, which is p...
Regucalcin plays an inhibitory role in various cell signaling systems, including calcium signaling. Recent studies have demonstrated its role as a cancer-suppressing protein. Notably, extracellular regucalcin, which is present in the serum, has been shown to suppress cancer cells in vitro, suggesting a role for regucalcin in the cancer microenvironment. Neuroblastoma is the most common extracranial solid tumor and has a high rate of metastases. Treatment strategies vary in intensity depending on the aggressiveness of the disease. Advanced tools may be needed. This study investigates the effects of extracellular regucalcin on SK-N-SH human neuroblastoma cells in vitro. The neuroblastoma cells were cultured in DMEM containing 10% FBS with various concentrations of extracellular regucalcin (0.001, 0.01, 0.1, 1, or 10 nM). Extracellular regucalcin (1 or 10 nM) inhibited the growth and colony formation of neuroblastoma cells without causing cell death. It blocked the stimulatory effects of epidermal growth factor (EGF) on neuroblastoma cell proliferation. Regucalcin did not alter EGF receptor levels. Treatment with regucalcin decreased the expression levels of Ras, PI3-kinase 100α, Akt, MAPK, phospho-MAPK, and mTOR, which are associated with promoting cell growth. This resulted in a reduction in cancer cell growth. Additionally, culturing with regucalcin inhibited the production of reactive oxygen species involved in cell damage. Furthermore, regucalcin treatment suppressed metastatic activity, including the adhesion, invasion, and migration of neuroblastoma cells. Taken together, these results suggest that extracellular regucalcin may exhibit anticancer activity against SK-N-SH human neuroblastoma cells in vitro, offering a new strategy for neuroblastoma treatment.
Neutrophilic LGALS2 drives tuberculosis susceptibility by regulating Th2 polarization via the IFN-γ-HLA-II-CD4 axis.
Wu W, Xing F, Xue Y … +4 more , Gao S, Zhang H, Fu Y, Yi Z
Cell Signal · 2026 Jul · PMID 42385923 · Publisher ↗
Th1/Th2 immune imbalance constitutes a critical mechanism underlying Mycobacterium tuberculosis (Mtb)-mediated immune evasion. Nevertheless, the specific regulatory mechanism of neutrophils, the pivotal upstream innate i...
Th1/Th2 immune imbalance constitutes a critical mechanism underlying Mycobacterium tuberculosis (Mtb)-mediated immune evasion. Nevertheless, the specific regulatory mechanism of neutrophils, the pivotal upstream innate immune cells, remains poorly elucidated in this imbalance. This study integrates multi-omics technologies, combines an in vitro primary cell co-culture model and clinical samples for verification, and systematically elucidates the core mechanism by which neutrophils regulate Th1/Th2 immune imbalance in tuberculosis (TB). Our data demonstrate that LGALS2 is highly expressed in neutrophils and serves as a key susceptibility factor facilitating TB development and progression. A remarkable reduction in the Th1/Th2 ratio was observed in TB patients, reflecting disrupted Th1/Th2 immune homeostasis. Suppression of neutrophilic LGALS2 successfully restored the distorted immune balance. Mechanistically, elevated LGALS2 induces Th2 differentiation through the IFN-γ/HLA-II/CD4 axis, whereas loss of LGALS2 enhances TCR-cascade signaling to promote Th1 differentiation. Further epigenetic analysis reveals that the high expression of LGALS2 is attributed to aberrant methylation of its gene promoter. Taken together, this study provides critical mechanistic clues to two longstanding puzzles in TB immunology: the elusive mechanism driving TB-associated Th1/Th2 imbalance and the poorly understood function of innate neutrophils. We uncover a neutrophil-specific epigenetic axis: promoter hypermethylation upregulates LGALS2, which disturbs Th1/Th2 balance through distinct IFN-γ/HLA-CD4 and TCR signaling cascades to heighten TB susceptibility. The findings provide potential novel targets for TB precision immunotherapy.
Diosgenin alleviates radiation nephropathy by suppressing renal mTORC1 signalling with concomitant effects on the gut and liver.
Hu C, Hong G, Li Z … +7 more , Qi S, Li J, Luo J, Li M, Li H, Ma J, Lin Y
Cell Signal · 2026 Jun · PMID 42372898 · Publisher ↗
BACKGROUND: Radiation nephropathy is a progressive inflammatory and fibrotic condition lacking effective therapies. The underlying cellular signalling mechanisms and their potential systemic involvement remain poorly def...
BACKGROUND: Radiation nephropathy is a progressive inflammatory and fibrotic condition lacking effective therapies. The underlying cellular signalling mechanisms and their potential systemic involvement remain poorly defined. METHODS: We integrated single-cell transcriptomics, network pharmacology, molecular docking and dynamics simulations, and in vivo validation in a murine model of whole-body irradiation. RNA sequencing data from healthy and irradiated mouse kidneys were analyzed to map cell-type-specific signalling activities of mTORC1, endoplasmic reticulum (ER) stress, and inflammation, as well as intercellular communication. Mice received diosgenin at 30 or 100 mg/kg/d by orally or rapamycin at 2 mg/kg/d by intraperitoneal injection for 7 days before and 28 days after 5 Gy X-ray irradiation. Renal function, histopathology, oxidative stress, inflammatory cytokines, intestinal barrier integrity, hepatic inflammation, and gut microbiota were assessed. RESULTS: Bulk transcriptomics and network pharmacology identified mTOR as a core target. Single-cell analysis revealed radiation-induced mTORC1 activation in proximal tubular cells and immune cells, coupled with ER stress and inflammation. Molecular docking predicted high binding affinity between diosgenin and mTOR. Molecular dynamics simulations confirmed stable diosgenin-mTOR binding over 100 ns. In vivo, diosgenin suppressed renal mTORC1 activity, reduced ER stress, and macrophage infiltration, lowered serum TNF-α, IL-1β, and IL-6, and decreased serum urea and creatinine by approximately 30.25% and 26.20%, respectively. Diosgenin alleviated renal fibrosis, restored colonic occludin expression by 1.5-fold, decreased hepatic F4/80-positive cells by 75.32%, reversed gut dysbiosis including suppression of Pseudomonadota, and these effects were similar to those of rapamycin, an mTOR inhibitor. CONCLUSION: Diosgenin alleviates radiation nephropathy by suppressing mTORC1 signalling while exerting concomitant effects on the gut and liver. These findings establish a multi-omics and single-cell framework for radiation nephropathy and support diosgenin as a candidate for translational research.
Glycine induces MafG to regulate glutathione metabolism, inhibit chondrocyte ferroptosis, and upregulate plectin to improve osteoarthritis.
Li Y, Lv Y, Zhang J … +6 more , Yu H, Tang Y, Chen G, Su J, Ji R, Zhao W
Cell Signal · 2026 Jun · PMID 42372897 · Publisher ↗
To investigate the mechanism by which glycine inhibits chondrocyte ferroptosis and improves osteoarthritis (OA), primary rat chondrocytes were pre-treated with glycine prior to interleukin-1β (IL-1β) stimulation. Cellula...
To investigate the mechanism by which glycine inhibits chondrocyte ferroptosis and improves osteoarthritis (OA), primary rat chondrocytes were pre-treated with glycine prior to interleukin-1β (IL-1β) stimulation. Cellular viability, apoptosis, senescence, reactive oxygen species (ROS), lipid peroxide, Fe, and GSH level were determined. Transcriptomic analysis, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assay were employed to confirm the MafG-Plectin regulatory axis. Loss-of-function experiments using siRNA targeting Plectin or MafG validated the functional necessity of this axis. A rat OA model was established by anterior cruciate ligament transection (ACLT), and glycine was injected intra-articularly. Glycine pretreatment significantly improved IL-1β-induced chondrocyte dysfunction, inhibited ROS accumulation, lipid peroxidation, and Fe overload, and upregulated SLC7A11 and GPX4. Glycine upregulated MafG, which directly bound the Plectin promoter to promote Plectin transcription. Silencing of either MafG or Plectin reversed glycine's protective effects, confirming the MafG-Plectin axis as an essential operative module. In OA rats, glycine alleviated cartilage degradation, improved bone microstructure, and upregulated MafG, Plectin, and GPX4; these effects were abolished by si-MafG. Collectively, glycine inhibits chondrocyte ferroptosis and improves OA through a dual mechanism involving MafG-mediated GSH synthesis and MafG-dependent Plectin upregulation, providing a potential therapeutic target for OA.
SHC4 suppresses ferroptosis and promotes sorafenib resistance in hepatocellular carcinoma by disrupting the interaction between NCOA4 and FTH1.
Chai D, Zhang J, Dong K … +6 more , Yu J, Zhang X, Kuang T, Feng J, Li M, Wang W
Cell Signal · 2026 Oct · PMID 42364863 · Publisher ↗
Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in hepatocellular carcinoma (HCC) progression and is now recognized as a key mechanism underlying the antitumor activity of sorafenib. Src...
Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in hepatocellular carcinoma (HCC) progression and is now recognized as a key mechanism underlying the antitumor activity of sorafenib. Src homology and collagen protein 4 (SHC4), an adaptor protein implicated in oncogenic signaling and tumor progression, has recently emerged as a potential regulator in multiple cancers; however, its involvement in ferroptosis and sorafenib response remains unclear. Our preliminary data showed that sorafenib treatment alters SHC4 expression in both clinical tissues and HCC cell models, suggesting a possible connection between SHC4 and ferroptotic susceptibility. These findings prompted us to investigate whether SHC4 modulates ferroptosis and contributes to sorafenib resistance. Here, we found that SHC4 decreased the anti-tumor activity of sorafenib by reducing ferroptosis both in vitro and in vivo. SHC4 diminished ROS and MDA production, lowered intracellular iron levels, enhanced GSH levels, and regulated the expression of Nrf2, xCT, and GPX4 proteins associated with antioxidant stress. In addition, SHC4 interacts with the 383-522 fragment of NCOA4, thereby blocking the association between NCOA4 and FTH1. This interference reduces the lysosomal degradation of FTH1, leading to decreased intracellular Fe levels and ultimately suppressing ferroptosis. Clinically, the concurrent overexpression of SHC4 and FTH1 has been identified as a potential prognostic marker for poor outcomes in patients with hepatocellular carcinoma. Collectively, our study demonstrates the pivotal role of SHC4 in regulating ferroptosis in hepatocellular carcinoma and highlights its potential as a novel therapeutic target for overcoming sorafenib resistance.
Post-translational modifications in triple-negative breast cancer: research status and translation challenges.
Wang JM, Zhou Y, Li F … +1 more , Ding Y
Cell Signal · 2026 Oct · PMID 42364862 · Publisher ↗
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 amplification. The lack of therapeutic targets contributes to...
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 amplification. The lack of therapeutic targets contributes to its poor prognosis and limited treatment options. Nowadays, there is growing evidence that post-translational modifications (PTMs) play important roles in shaping the aggressive nature, immune microenvironment, and metabolic pathways in many tumor types. Here, in this review, we comprehensively summarized the roles of key PTMs, including phosphorylation, ubiquitination, acetylation, protein methylation, SUMOylation, lactylation, glycosylation, β-hydroxybutyrylation, and succinylation in TNBC. We discussed detection technologies for each PTM, detailed their molecular mechanisms and biological functions, and suggested therapeutic strategies targeting these modifications. Moreover, we reviewed PTM crosstalk networks and their clinical implications. Finally, we discussed the translational challenges and propose solutions for developing PTM-based diagnostics and therapies for TNBC. An evidence stratification framework was applied to grade the strength of the reviewed findings, distinguishing mechanistically validated, correlative, and clinically actionable evidence.
PDK4-dependent lactate production and lactylation promote renal calcium oxalate crystal-induced EMT and mitochondrial dysfunction via the TGF-β/SMAD3/GPX4 axis.
Zhang B, Liu K, Fan R … +2 more , Zeng Y, Li H
Cell Signal · 2026 Jun · PMID 42364861 · Publisher ↗
BACKGROUND: Urolithiasis is a highly prevalent urinary system disease imposing a significant global health burden, with calcium oxalate (CaOx) stones constituting the majority of cases. The underlying metabolic and epige...
BACKGROUND: Urolithiasis is a highly prevalent urinary system disease imposing a significant global health burden, with calcium oxalate (CaOx) stones constituting the majority of cases. The underlying metabolic and epigenetic mechanisms driving CaOx stone formation remain incompletely understood. METHODS: Through integrated single-cell, spatial, and bulk transcriptomic analyses, this study identified PDK4 as a key gene upregulated by CaOx stones in renal proximal tubular epithelial cells (PTECs). In vitro and in vivo models of CaOx stones were established using calcium oxalate monohydrate (COM) treatment and glyoxylic acid (Gly) induction, respectively. Genetic and pharmacological inhibition of PDK4, knockdown of lactate dehydrogenase a (LDHA), and TGF-β inhibitor SB-431542 intervention were employed. Assays for lactate measurement, protein lactylation, epithelial-mesenchymal transition (EMT) markers, mitochondrial function, chromatin immunoprecipitation (ChIP)-qPCR for SMAD3 binding to the GPX4 promoter, and signaling pathway components (TGF-β/SMAD3/GPX4) were performed. RESULTS: CaOx stones upregulated PDK4 expression in PTECs, leading to glycolytic dysfunction and lactate accumulation. Elevated lactate drove protein lactylation, which subsequently activated the TGF-β/SMAD3 signaling and enhanced SMAD3 binding to the GPX4 promoter to repress GPX4 transcription. This cascade ultimately exacerbated CaOx stone-induced epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction in PTECs. Conversely, pharmacological inhibition of TGF-β signaling alleviated CaOx stone-induced renal injury, EMT, and mitochondrial dysfunction in vivo. Inhibition of PDK4 or reduction of lactate production blocked this axis and attenuated the pathological processes. CONCLUSION: These findings delineate a novel PDK4/lactate/lactylation/TGF-β/SMAD3/GPX4 metabolic-epigenetic regulatory axis in CaOx stone-induced renal injury. This pathway provides new mechanistic insights and identifies potential therapeutic targets for nephrolithiasis.
O-GlcNAcylation-mediated glycolytic reprogramming of CD4 T cells contributes to type H vessel impairment in diabetic osteoporosis.
Jiang Y, Dai Y, Li X … +4 more , Cui Y, Liu H, Hasegawa T, Li M
Cell Signal · 2026 Oct · PMID 42361945 · Publisher ↗
Diabetic osteoporosis (DOP) is a metabolic bone disease characterized by skeletal fragility and impaired angiogenesis-osteogenesis coupling, in which type H vessel impairment has emerged as an important pathological feat...
Diabetic osteoporosis (DOP) is a metabolic bone disease characterized by skeletal fragility and impaired angiogenesis-osteogenesis coupling, in which type H vessel impairment has emerged as an important pathological feature. While adaptive immunity is known to regulate bone homeostasis, the immunometabolic mechanisms driving vascular dysfunction in DOP remain elusive. Here, we investigated whether pathological metabolic reprogramming of CD4 T cells is linked to type H vessel impairment in DOP. CD4 T cells from DOP mice exhibited enhanced glycolytic activation accompanied by increased hexokinase 2 (HK2) expression and elevated O-GlcNAcylation. In vitro, high glucose and palmitic acid (HGPA) treatment was associated with increased HK2 O-GlcNAcylation, HK2 stabilization, mitochondrial localization, and enhanced glycolytic activity in CD4 T cells. These metabolic alterations were accompanied by senescence-associated and pro-inflammatory phenotypes, including upregulation of P53, P16, PD-1, IL-6, and IL-17A, as well as enhanced T helper 17 (Th17) polarization. Co-culture experiments showed that HGPA-treated CD4 T cells were associated with impaired endothelial viability, migration, tube formation, and reduced VEGFA/VEGFR2 expression. Pharmacological inhibition of O-GlcNAcylation or glycolysis partially attenuated CD4 T cell dysfunction and improved endothelial angiogenic function. Collectively, these findings suggest that O-GlcNAcylation-associated HK2 glycolytic activation may contribute to CD4 T cell dysfunction and type H vessel impairment in DOP. Targeting this immunometabolic pathway may represent a potential therapeutic strategy for diabetic skeletal complications.
SPP1 promotes fatty acid synthesis in macrophages to drive silicosis.
Chen X, Li T, Wang J … +14 more , Yang X, Sun X, Jin F, Li Y, Mao N, Gao X, Wei Z, Zhu Y, Xu D, Li J, Xue L, Yang F, Xu H, Cai W
Cell Signal · 2026 Oct · PMID 42349708 · Publisher ↗
Osteopontin (SPP1) plays a critical role in the initiation and progression of silicosis, but whether macrophage-derived SPP1 regulates lipid metabolism during silicosis remains unclear. In this study, RNA sequencing of l...
Osteopontin (SPP1) plays a critical role in the initiation and progression of silicosis, but whether macrophage-derived SPP1 regulates lipid metabolism during silicosis remains unclear. In this study, RNA sequencing of lung tissues from silicotic mice and silica-stimulated alveolar macrophages identified Spp1 as a differentially expressed gene, and pathway enrichment analysis revealed significant enrichment of lipid metabolism-related signaling pathways. Using in vivo and in vitro models of silicosis, we assessed changes in SPP1 expression and key fatty acid synthesis markers. Silica stimulation increased SPP1 expression, induced lipid droplet formation, and upregulated fatty acid synthesis-related proteins. Subsequent in vitro experiments, including Spp1 knockdown, overexpression, and recombinant protein treatment, demonstrated that Spp1 knockdown effectively suppressed silica-induced lipid droplet formation and fatty acid synthesis. Mechanistically, SPP1 activated the fatty acid synthesis pathway by binding to its receptor CD44, thereby promoting SREBP-1 processing and nuclear translocation. Notably, Cd44 silencing abrogated SPP1-induced lipid droplet formation, the upregulation of fatty acid synthesis enzymes, and the production of pro-inflammatory cytokines (TNF-α and IL-6). Moreover, macrophage-specific knockout of Spp1 significantly alleviated pulmonary fibrosis, improved lung function, and inhibited the fatty acid synthesis pathway in vivo. Collectively, this study elucidates a novel mechanism by which SPP1 regulates macrophage fatty acid metabolism through the CD44/SREBP-1 axis, providing a mechanistic basis for targeting SPP1 in silicosis treatment.
β-TrCP targets nucleolin and modulates phase separation to restrict ribosome biogenesis in myocardial infarction hearts.
Tu J, Zhang H, Lu T … +7 more , Zhou A, Zhang Y, Li A, Liu B, Yu XY, Xu Y, Li Y
Cell Signal · 2026 Jun · PMID 42349707 · Publisher ↗
Myocardial infarction (MI) remains a significant global health challenge, as limited long-term efficacy of coronary interventions is largely due to inadequate cardiomyocyte (CM) regeneration. Ribosome biogenesis, a key d...
Myocardial infarction (MI) remains a significant global health challenge, as limited long-term efficacy of coronary interventions is largely due to inadequate cardiomyocyte (CM) regeneration. Ribosome biogenesis, a key driver of cell regeneration, and Nucleolin (NCL), a cardioprotective protein, have emerged as crucial factors in post-MI recovery. While liquid-liquid phase separation (LLPS) plays a dynamic role in cellular regulation, its impact on NCL-mediated ribosome biogenesis following MI remains unclear. Using Ribo-Halo, Ribo-disome, and AgNOR staining to map ribosome biogenesis, along with co-immunoprecipitation, molecular docking, FRAP, and confocal imaging to examine NCL ubiquitination and LLPS dynamics, we investigated these mechanisms. In MI mice and hypoxic cells, we identified an inverse correlation between the E3 ubiquitin ligase β-TrCP and NCL levels. Our Co-IP results demonstrate a functional interaction between β-TrCP and NCL in cytoplasm, and hypoxia induced LLPS transition of NCL in nuclear. NCL depletion impaired ribosome biogenesis and CM renewal. Our findings reveal NCL depletion-mediated by β-TrCP and LLPS formation as a key mechanism hindering cardiac repair post-MI. This study provides valuable insights and introduces potential therapeutic target for treating MI.
Pan-cancer analysis reveals the prognostic relevance of NUP54 and its association with HIF-1α-related glycolytic phenotypes in lung adenocarcinoma.
Cheng P, Song C, Han Q … +2 more , Yang H, Fan R
Cell Signal · 2026 Oct · PMID 42349706 · Publisher ↗
The role of the nuclear pore protein NUP54 in tumorigenesis and progression remains unclear. By integrating multiomics data from TCGA, GTEx, CPTAC, and other sources, in this study, the first pan-cancer landscape of NUP5...
The role of the nuclear pore protein NUP54 in tumorigenesis and progression remains unclear. By integrating multiomics data from TCGA, GTEx, CPTAC, and other sources, in this study, the first pan-cancer landscape of NUP54 was systematically delineated: its mRNA and protein expression levels are significantly upregulated in most types of cancer, including lung adenocarcinoma, hepatocellular carcinoma, and gastric cancer. It has a high diagnostic value across several types of cancer, including cholangiocarcinoma and pancreatic cancer. Its prognostic value has high tissue specificity: serving as an independent risk factor in low-grade glioma, lung adenocarcinoma, and pancreatic cancer, while protecting against renal clear cell carcinoma. Focusing on lung adenocarcinoma, multi-cohort clinical assessment, single-cell transcriptomics analysis, and functional experiments confirmed that high expression of NUP54 is an independent predictor of poor patient prognosis and significantly promotes the proliferation of cancer cells, colony formation, and in vivo tumorigenesis. NUP54 activates the HIF-1α signaling pathway to upregulate key glycolytic molecules LDHA, PKM2, and GLUT1, thereby driving glucose uptake, lactate production, and high ATP levels to promote metabolic reprogramming. This NUP54-associated phenotype was attenuated by the HIF-1α inhibitor PX-478 in vitro and in vivo. Overall, this study identifies NUP54 as a potential prognostic biomarker in LUAD and suggests that the NUP54/HIF-1α/glycolysis-related pathway may represent a biological mechanism worthy of further investigation.
The effects of long-term aerobic exercise on prostate cancer-induced adipose tissue wasting: Browning to the rescue?
Moreira-Pais A, Moreira-Gonçalves D, Oliveira PA … +9 more , Seixas F, Brandão SR, Neuparth MJ, Vitorino R, Santos LL, Fardilha M, Duarte JA, Ferreira R, Nogueira-Ferreira R
Cell Signal · 2026 Oct · PMID 42349705 · Publisher ↗
The loss of adipose tissue has been emerging as a key component of cancer-related body wasting. One of the underlying causes suggested for this loss is the browning of the white adipose tissue. However, exercise, a promi...
The loss of adipose tissue has been emerging as a key component of cancer-related body wasting. One of the underlying causes suggested for this loss is the browning of the white adipose tissue. However, exercise, a promising therapeutic strategy for cancer-related body wasting, might also promote white adipose tissue browning. It remains unclear how similar or distinct the browning process and its effects are when triggered by exercise in cancer compared to cancer alone. This study investigated the retroperitoneal adipose tissue remodeling in prostate cancer-induced body wasting with and without long-term aerobic exercise. For that, a chemically- and hormonally-induced prostate cancer protocol was implemented in male rats as a cancer-induced body wasting model, and a treadmill exercise protocol of 53 weeks was used as long-term aerobic exercise. Sedentary or exercised tumor-free rats were used as controls. The results revealed that prostate carcinogenesis induced body wasting and reduced the cross-sectional area (CSA) of adipocytes in retroperitoneal adipose tissue without increasing the levels of browning markers, suggesting wasting without browning. Aerobic exercise attenuated the development of prostate carcinogenesis-induced body wasting and decreased the CSA of the adipocytes while increasing their number. The reduced CSA was correlated with increased retroperitoneal adipose tissue levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and uncoupling protein 1 (UCP1), disclosing molecular adaptations compatible with an adipose tissue browning phenotype. These results suggest that long-term aerobic exercise induces adipose tissue remodeling that may counteract cancer-induced body wasting, highlighting the potential of physical activity in managing cancer-related metabolic changes.
Multiple regulatory roles of UNC93B1 in innate immunity.
Yi L, Li Y, Xiao X … +5 more , Li J, Yang Z, Zhang Y, Xue M, Zheng C
Cell Signal · 2026 Oct · PMID 42336340 · Publisher ↗
Uncoordinated 93 homolog B1 (UNC93B1) is a key innate immune regulator that affects the function of pattern recognition receptors. UNC93B1 is responsible for governing the intracellular trafficking and activation of nucl...
Uncoordinated 93 homolog B1 (UNC93B1) is a key innate immune regulator that affects the function of pattern recognition receptors. UNC93B1 is responsible for governing the intracellular trafficking and activation of nucleic acid-sensing TLRs. Recently, UNC93B1 was shown to regulate the cGAS/STING signaling pathway. As a result, UNC93B1 is a promising therapeutic target for various human diseases. In this review, we provide an update on new findings establishing the regulatory role of UNC93B1 in innate immunity, including the antibacterial activity of neutrophils, the PRR-mediated signaling pathway, and its specific role in autoimmune illnesses and severe viral infectious diseases. A thorough assessment of the role of UNC93B1 in innate immune regulation will allow us to identify possible novel therapeutic targets in UNC93B1-associated disorders.
NDUFA4L2 acts as a mitochondrial checkpoint against ferroptosis in hypoxic clear cell renal cell carcinoma.
Sun X, Zhou Q, Wu Y … +3 more , Qian W, Ma J, Zhang T
Cell Signal · 2026 Oct · PMID 42331208 · Publisher ↗
This study aimed to define the functional role of the HIF-1α target gene NDUFA4L2 in clear cell renal cell carcinoma (ccRCC), specifically its regulation of mitochondrial function and the ferroptosis cell death pathway....
This study aimed to define the functional role of the HIF-1α target gene NDUFA4L2 in clear cell renal cell carcinoma (ccRCC), specifically its regulation of mitochondrial function and the ferroptosis cell death pathway. Through TCGA data analysis and in vitro and in vivo models, we confirmed that HIF-1α induces NDUFA4L2 expression and mitochondrial localization. Using shRNA-mediated knockdown combined with rescue experiments employing the ferroptosis inhibitor ferrostatin-1 and the mitochondrial antioxidant mitoTEMPO, we demonstrated that silencing NDUFA4L2 triggered mitochondrial lipid peroxidation, altered mitochondrial ultrastructure, and suppressed proliferation via a mitochondria-associated ferroptotic mechanism. Mechanistically, NDUFA4L2 functioned parallel to Lactate Dehydrogenase B (LDHB); their genetic or pharmacological co-inhibition synergistically enhanced ferroptosis and suppressed cell viability in vitro and tumor growth in vivo, associated with elevated ferroptosis markers (PTGS2, 4-HNE). Furthermore, NDUFA4L2 knockdown sensitized tumors to radiotherapy by amplifying ferroptotic cell death. In conclusion, NDUFA4L2 is a critical suppressor of mitochondria-associated ferroptosis in ccRCC, acting cooperatively with LDHB to maintain redox homeostasis, and targeting the NDUFA4L2/LDHB axis represents a promising therapeutic strategy, particularly in combination with radiotherapy.
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