Journal of Cellular Physiology最新文献

The global rise in obesity has coincided with an alarming increase in early-onset cancers and other chronic noncommunicable diseases, underscoring the urgent need to understand the underlying mechanisms linking excess body weight with disease pathogenesis. While genetic factors account for disease risk, environmental and dietary influences, particularly those associated with Western hypercaloric diets, play a dominant role in shaping metabolic health. Obesity-driven insulin resistance and chronic inflammation are now recognized as central contributors to a wide range of pathologies, including cardiovascular disease, type 2 diabetes, fatty liver, and multiple cancer types. Emerging evidence suggests that disrupted insulin signaling, altered lipid metabolism, and chronic inflammation converge to promote a tumor-permissive tissue microenvironment. This review examines the mechanistic links between insulin signaling, lipid metabolism, and inflammation as the causality of increased cancer risk in obesity.

The progression of acute kidney injury (AKI) to chronic kidney disease (CKD) represents a unique renal disease scenario, yet its exact mechanisms remain unclear. The transport of renal metabolic byproducts plays a crucial role in maintaining systemic homeostasis and the repair process. The glutathione-based lipid oxidation–reduction system is essential for preserving cellular function. However, the relationship between the disruption of the redox system during the AKI-CKD transition and renal transport proteins remains unclear. We investigated the mechanisms by which the transport protein multidrug resistance-associated protein 1 (MRP1) mediates the destruction of the redox system during renal ischemia-reperfusion injury (IRI) and devised interventions related to renal ferroptosis. Transcriptome analysis and a unilateral kidney IRI model were employed to explore changes in MRP1 expression during the AKI-CKD process. Functional experiments simulating in vivo renal IRI were conducted using Carbonyl Cyanide m-Chlorophenylhydrazine (CCCP)-treated renal tubular epithelial cells. MK571(MRP1 inhibitor) and Fer-1 were used to inhibit MRP1 and ferroptosis, respectively. Kidney tissue damage and fibrosis area were evaluated using staining methods like KIM1 and Masson. In the renal IRI model, upregulation of the transport protein MRP1 expression in renal tissue was observed. MRP1 is responsible for transporting glutathione outside the cell. MK571 significantly inhibited the AKI- CKD transition and immune cell infiltration. Both the deletion or inhibition of MRP1 can also alleviate ferroptosis. However, the combined use of MK571 and Fer-1 did not show additional kidney protective effects. Elevated expression of the renal transport protein MRP1 during renal IRI induces the extracellular leakage of glutathione, leading to ferroptosis. Inhibiting MRP1 can slow down renal ferroptosis and the progression from AKI-CKD.

MicroRNAs (miRNAs) have been demonstrated to be involved in various cellular biological processes. However, their impacts on apoptosis and oxidative stress in ovarian granulosa cells (GC) remain largely unknown. Here, we identified that miR-30b was transcriptionally activated in sow GCs during follicular atresia or from an in vitro oxidative stress GC model, leading to the specific upregulation of miR-30b-3p, a highly conserved miRNA located within sow reproductive trait locus and predominantly expressed in the cytoplasm of GCs. Notably, miR-30b-3p levels in follicles were negatively correlated with the E2/P4 ratio and the SOD/MDA index. Functional analysis revealed that miR-30b-3p induced the apoptosis and drove oxidative stress in sow GCs. Mechanistically, miR-30b-3p inhibits the expression of SMAD3 (antiapoptotic factor) and SOD2 (antioxidant enzyme) by directly binding to their 3′-UTR. Furthermore, restoration of SMAD3 and SOD2 expression effectively suppressed the proapoptotic and pro-oxidative functions of miR-30b-3p. In addition, KLF5 specifically activates the transcription of miR-30b in sow GCs by acting as a transcription factor, resulting in its upregulation during follicular atresia and under oxidative stress. More importantly, ROC analysis indicated that miR-30b-3p level in GCs can serve as an effective biomarker to evaluate follicular development and antioxidant capacity. Our findings elucidate the critical role of miR-30b-3p in regulating GC apoptosis and oxidative stress, as well as its functional targets and expression regularity, suggesting that inhibition of miR-30b-3p is a potential approach for maintaining follicular development, enhancing ovarian antioxidant, and improving sow fertility.

Mettl14, a key component of the m6A methyltransferase complex, plays a crucial role in regulating mRNA stability and splicing. Reduced expression of Mettl14 is associated with hepatocellular carcinoma and liver regeneration, yet the molecular mechanisms by which it regulates the hepatocyte cell cycle remain unclear. Using RNA-Seq and MeRIP-Seq in liver-specific Mettl14 knockout mice, we found that Mettl14 deficiency stabilizes Fam32a mRNA through m6A modifications, resulting in increased Fam32a protein levels. Elevated Fam32a expression accelerates the G1/S transition by modulating Cdkn1a splicing, specifically downregulating its variant 2. These findings uncover a novel m6A-dependent mechanism that regulates hepatocyte cell cycle progression and highlight the previously unrecognized role of Fam32a in promoting the G1/S transition.

Disulfidptosis is a newly identified form of programmed cell death closely associated with cystine metabolism abnormalities and cytoskeletal damage. Orthopedic diseases, such as degenerative conditions including intervertebral disc degeneration, osteoporosis, osteoarthritis, and malignant bone tumors like osteosarcoma, all involve imbalances in the immunometabolic microenvironment. The triggering conditions for disulfidptosis, such as high expression of SLC7A11 and glucose deprivation, are highly correlated with the pathaological features of orthopedic diseases and associated immune dysregulation. However, there is currently a lack of systematic understanding regarding the regulatory networks, molecular markers, and intervention strategies of disulfidptosis in orthopedic diseases, and the specific mechanisms by which it contributes to disease onset and progression remain unclear. This review systematically summarizes the bidirectional immunometabolic regulatory molecular mechanisms, pathological associations, and potential therapeutic strategies of disulfidptosis in orthopedic degenerative diseases and bone tumors. By analyzing the immunometabolic regulatory networks of key molecules such as SLC7A11, TXNRD1, and RPN1, we propose immune-aware precision strategies combining disulfidptosis-targeted metabolic intervention with checkpoint blockade immunotherapy. This review fills the gap in the research of disulfidptosis in orthopedic diseases, providing new insights for a deeper understanding of the molecular mechanisms underlying these conditions, while establishing a theoretical framework for developing precise therapeutic strategies based on the regulation of disulfidptosis.

Gastric cancer is the fifth most common malignancy and the fourth leading cause of cancer-related mortalities worldwide. Understanding the mechanisms driving tumor growth and metastasis in gastric cancer is essential for the development of effective therapeutic strategies. In this regard, it is well-established that CD200, a glycoprotein that binds to the CD200 receptor, has notable immunosuppressive effects. The extracellular domain of CD200 is secreted into the tumor microenvironment (TME), wherein it promotes cancer progression. However, although CD200 is highly expressed in several types of cancers, the details of its intracellular roles in tumor progression remain poorly understood. In this study, we investigated the biological function and mechanism of action of CD200 in gastric cancer. Public datasets from GSE and TCGA revealed that CD200 is overexpressed in gastric cancer and that its expression is correlated with cancer stage and metastasis. Functionally, we found that CD200 enhances cell proliferation, migration, and invasion, and also promotes the expression of epithelial-mesenchymal transition (EMT)-related genes. Mechanistically, CD200 was demonstrated activate the WNT/β-catenin signaling pathway by inducing β-catenin activation. Notably, we established that the cytoplasmic domain of CD200 binds directly to β-catenin, thereby facilitating its nuclear translocation. The CD200/β-catenin/TCF4 complex subsequently promotes the transcription of β-catenin target and EMT-related genes. Collectively, our findings in this study revealed that the cytoplasmic domain of CD200 interacts with β-catenin, thereby promoting the transcriptional activation of β-catenin target genes and inducing tumor growth and metastasis in gastric cancer. These findings accordingly indicate that CD200 may serve as a potential therapeutic target for the treatment of gastric cancer.

As a major modulator of cardiac function, intracellular pH (pH_i) is tightly controlled by sarcolemmal acid–base transporters to within narrow limits (7.1–7.3). Na⁺/H⁺ exchanger (NHE1) and Na⁺/HCO₃⁻ cotransporter (NBC) are the main acid-extruding membrane proteins; the latter is further subdivided into electrogenic (NBCe1/NBCe2) and electroneutral (NBCn1) isoforms. In the underperfused heart, acid disturbances are often accompanied by hypoxia, but their interplay on cardiac NBC activity is unknown. Here, we studied the effect of acute (1 mM dithionite and 100% N₂, 10 min) and long-term hypoxia (1% O₂, 48 h) on sarcolemmal NBC activity using fluorimetric assays in mouse atrial-derived HL-1 cells and primary rat cardiomyocytes. NBCe1 and NBCn1 transcripts were detected in HL-1 cells. Ensemble NBC activity, defined as the HCO₃⁻-dependent acid-extrusion flux, was promptly inhibited under acute anoxia. In contrast, pH_i-sensitivity of NBC flux was increased after long-term hypoxia, likely an adaptive response. This increase was not due to buffering capacity changes but was mimicked by dimethyloxalylglycine (1 mM, DMOG), which stabilizes hypoxia inducible factor under normoxic conditions. Hypoxia affected neither NBCn1 nor NBCe1 protein levels, indicating a modulatory effect on transporter activity. The contribution of electrogenic (NBCe1) and electroneutral (NBCn1) isoforms, dissected from fluxes generated under hyperkalemia, showed that long-term hypoxia selectively raised NBCn1 activity. This effect was blocked by U0126, an inhibitor of extracellular signal-regulated kinase 1/2, implicating phosphorylation. Our results show that acute anoxia and prolonged hypoxia regulate NBC-dependent flux by distinct mechanisms ostensibly to retain pH control under the combination of acidosis and hypoxia.