Hepatocellular carcinoma (HCC) is an aggressive malignant tumor with poor prognosis due to its strong metastatic potential. Studies linked osteopontin (OPN) to increased HCC metastasis. However, the mechanisms, especially those involving exosomes, are not well elucidated. This study investigates how OPN influences HCC cells behavior via exosome mediation. A stable HCC cell line overexpressing OPN, named SMMC-OPN, was established. Co-culture experiment revealed that exosomes from SMMC-OPN cells enhanced the migration and invasion of the parental SMMC-7721 cells. RNA sequencing found the downregulation of miR-4660 in these exosomes, which targets LGALS3BP (galectin-3 binding protein), elevated in both SMMC-OPN cells and their exosomes. Treatment with SMMC-OPN exosomes resulted in an upregulation of LGALS3BP expression in SMMC-7721 cells. Notably, upon forced overexpression of miR-4660 in SMMC-OPN cells, miR-4660 was observed to be encapsulated in exosomes. Co-culture experiments demonstrated that exosomes containing miR-4660, derived from miR-4660-overexpressing SMMC-OPN cells, counter-acted the promigratory and invasive effects of SMMC-OPN exosomes on recipient SMMC-7721 cells. These findings suggest that the downregulation of miR-4660 in SMMC-OPN exosomes contributes to the enhanced metastatic potential of HCC through modulating LGALS3BP. Furthermore, miR-4660 delivery via exosomes inhibits OPN-promoted hepatoma cell aggression by targeting LGALS3BP, highlighting a potential therapeutic target against cancer metastasis.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are hallmarks of many ophthalmic diseases; however, they have traditionally been examined as isolated pathological processes. Recent evidence indicates that these organelles are inextricably coupled through mitochondria–endoplasmic reticulum contact sites, also known as mitochondria‐associated membranes (MAMs), which coordinate Ca2+ signaling, lipid transfer, mitochondrial dynamics, redox balance, and cell death decisions. Consequently, dysregulated ER–mitochondria communication has emerged as a key vulnerability that links the cellular stress responses among diverse ocular tissues, including lens epithelial cells, retinal ganglion cells, the retinal pigment epithelium, and corneal endothelial cells. In this review, we summarize the recent advances involving the molecular architecture and regulatory function of ER–mitochondria crosstalk. We focus on how the unfolded protein response signaling, pathological MAM remodeling, Ca2+ dysregulation, and disrupted mitochondrial quality control collectively drive disease progression. By integrating evidence from cataract, glaucoma, diabetic retinopathy, age‐related macular degeneration, and Fuchs endothelial corneal dystrophy, we reveal that these disorders are not driven by a uniform mechanism of organelle failure, but rather by the dominance of pathological nodes along the ER–mitochondria axis. We propose that ophthalmic diseases should be stratified based on these distinct failure nodes, which provides a mechanistic framework for developing therapeutics. Within this context, interventions targeting maladaptive ER stress, MAM destabilization, bioenergetic failure, or defective mitophagy should be considered complementary and context‐dependent strategies. By reframing ophthalmic disorders as diseases of inter‐organelle stress integration, this review positions the ER–mitochondria axis as a modifiable upstream determinant of ocular cell fate, which provides a foundation for stage‐specific precision therapies.

This study aims to explore the mechanism of action of the Bromodomain‐containing protein 4 (BRD4) inhibitor GNE‐987 in the treatment of pediatric T‐cell Acute Lymphoblastic Leukemia (T‐ALL), focusing on its effect in inhibiting T‐ALL cell proliferation by activating the HLA Complex P5 (HCP5) Super‐enhancer. Through bioinformatics approaches (including weighted gene co‐expression network analysis and least absolute shrinkage and selection operator regression analysis), key factor BRD4 was identified from the Gene Expression Omnibus database, along with its related regulatory genes and Super‐enhancer. In vitro experiments validated the regulatory effects of GNE‐987 on the expression of BRD4 and HCP5, and its impact on T‐ALL cell proliferation, colony formation, and apoptosis was assessed. Animal experiments further confirmed the efficacy of GNE‐987 in inhibiting T‐ALL progression by regulating HCP5. The results demonstrated that GNE‐987 significantly enhances the activity of the HCP5 Super‐enhancer and inhibits T‐ALL cell proliferation while promoting apoptosis by downregulating BRD4. This study suggests that BRD4 and HCP5 are potential therapeutic targets for T‐ALL, and GNE‐987 provides a novel therapeutic strategy by targeting this regulatory axis, laying the foundation for precision therapy in T‐ALL.

Lupus nephritis (LN), a renal manifestation of systemic lupus erythematosus, results from immune‐mediated kidney injury. The present study investigated how complement component 5a (C5a) and its receptor (C5aR1) regulate phosphatase and tensin homolog (PTEN) expression and the phosphoinositide 3‐kinase (PI3K)/AKT pathway during LN development. Using MRL/lpr mice as an LN model, we examined the expression of C5a, C5aR1, PTEN, and related proteins through Western blot, quantitative real‐time PCR, and immunohistochemistry. Treatment with a C5aR1 antagonist (C5aR1A) was administered to assess its effects on renal function and molecular parameters. Elevated expression of C5a and C5aR1 was detected in MRL/lpr mice, accompanied by reduced PTEN levels and enhanced PI3K/AKT signaling activity. Treatment with the C5aR1 antagonist (C5aR1A) restored PTEN expression, suppressed AKT phosphorylation, and improved renal function, reflected by lower serum creatinine and blood urea nitrogen concentrations. These findings suggest that the C5a/C5aR1 axis contributes to LN progression by regulating PTEN and the PI3K/AKT signaling pathway, offering potential therapeutic insights for LN treatment.

Paraptosis is a non‐apoptotic form of programmed cell death, distinct from classical apoptosis in morphology and mechanism. It has been implicated in tumor resistance and immune microenvironment remodeling, but its role in breast cancer (BC) remains unclear. We classified patients into two subtypes based on the expression of paraptosis‐related genes. Then, we systematically analyzed the prognosis and tumor microenvironment (TME) associated with these subtypes. In addition, we developed a risk score, named the paraptosis‐related risk score (PRRS). We comprehensively analyzed the correlation of paraptosis with BC prognosis, TME, immune score, and drug sensitivity. Then, we performed in vitro experiments to verify the effect of PI4KB on BC. The PRRS can effectively predict the prognosis and immunity of BC. Low PRRS was associated with a favorable prognosis, characterized by reduced tumor purity and enhanced immune cell infiltration. In addition, PRRS can help identify patients who are suitable for specific drug therapies. Finally, we found that PI4KB was highly expressed in BC. Knockdown of PI4KB expression significantly suppressed BC cell proliferation and migration. Our study establishes a robust framework for BC subtype classification and prognostic prediction, providing novel guidance for personalized therapeutic strategies.

The Joint Meeting commemorating the 25th anniversary of the International CCN Society (ICCNS) and the 5th anniversary of the Association for Research on Biosignaling and Communication (ARBIOCOM) will take place on December 13–17, 2025, in Nice, France. This multidisciplinary forum will bring together researchers in molecular and cellular biology, systems biology, translational medicine, and related fields to explore advances in intercellular communication and signal transduction. The program will include keynote lectures, thematic sessions, and attendee presentations spanning juxtacrine and paracrine interactions, extracellular matrix‐mediated signaling with emphasis on CCN proteins, endocrine and neuroendocrine regulation, immune‐modulatory circuits, extracellular vesicle biology, and systemic regulation by soluble factors. A special focus will address how dysregulated signaling drives cancer, musculoskeletal, cardiovascular, neurodegenerative, and developmental disorders. Sessions will encourage contributions using single‐cell and spatial transcriptomics, dynamic proteomics, and systems‐level approaches to map signaling dynamics in vivo. The meeting will also highlight pivotal role of the Journal of Cell Communication and Signaling (JCCS), the official ICCNS journal published by Wiley, as a leading platform for disseminating impactful research in biosignaling. This joint anniversary event will provide an international venue for advancing knowledge, fostering collaborations, and shaping the future of research in cell communication and signaling.

Abdominal aortic aneurysm (AAA) is a life‐threatening vascular disorder lacking effective pharmacological interventions. We identified CD5 molecule‐like (CD5L) as a regulator of macrophage polarization in AAA via the phosphoinositide 3‐kinase/protein kinase B/nuclear factor kappa B (PI3K/Akt/NF‐κB) pathway. Transcriptomic analyses (GSE47472 and GSE57691) and angiotensin II (AngII)‐infused apolipoprotein E‐deficient (ApoE−/−) mice showed CD5L upregulation, inversely correlated with M1 macrophage infiltration. In vitro CD5L overexpression reduced, whereas knockdown increased M1 polarization and pro‐inflammatory cytokines in RAW264.7 cells and human monocyte‐derived macrophages. In vivo, CD5L knockdown aggravated aortic dilation, vascular disruption, and inflammatory mediator expression. Pharmacological modulation confirmed PI3K/Akt as essential for CD5L's anti‐inflammatory action: LY294002 amplified, whereas PI3K activator 740Y‐P mitigated CD5L deficiency effects. RNA sequencing confirmed PI3K/Akt activation downstream of CD5L. These results define CD5L as an immunometabolic checkpoint that suppresses NF‐κB‐mediated inflammation, suggesting a therapeutic target for AAA.

This study investigates the impact of the CD2–CD58 signaling axis on effector T cell function and tumor metabolic crosstalk in breast cancer brain metastasis (BCBM) using single‐cell transcriptomic analysis. scRNA‐seq data analysis revealed the critical role of CD2–CD58 signaling between CD8+ T cells and tumor cells in BCBM. Functional assays demonstrated that CD2 knockdown inhibited cytotoxic T lymphocyte (CTL) proliferation, activation, and cytotoxicity, leading to impaired tumor cell recognition and enhanced proliferation, migration, and invasion. In vivo studies showed that CD2‐deficient CTLs promoted tumor growth and brain metastasis while affecting metabolic reprogramming by altering key enzyme expressions in pyrimidine biosynthesis and arginine metabolism pathways. The findings suggest that CD2 enhances CTL function against tumor cells and influences their metabolic states, highlighting the role of CD2 in remodeling the brain metastatic microenvironment in breast cancer.

Osteogenic differentiation of mesenchymal stem cells (MSCs) was strongly correlated with the progression of congenital tibial pseudoarthrosis (CPT). Activation of ferroptosis inhibited osteogenic differentiation of MSCs. ELAV-like RNA binding protein 1 (ELAVL1) is a key factor in promoting ferroptosis. This study aimed to elucidate the mechanism of ELAVL1 in the osteogenic differentiation of CPT periosteum-derived MSCs. Osteogenic differentiation of CPT periosteum-derived MSCs was detected by ARS and ALP staining. Fe2+ content and lipid reactive oxygen species content were measured using commercial kits. Molecular interactions were verified using RIP, RNA pulldown, and Co-IP. The ubiquitination level of homeobox gene D8 (HOXD8) was detected using Co-IP. Expression of ELAVL1 and tripartite motif containing 21 (TRIM21) was upregulated in CPT periosteum-derived MSCs, whereas HOXD8 expression was downregulated. Moreover, knockdown of ELAVL1 or TRIM21 inhibited ferroptosis and promoted osteogenic differentiation of CPT MSCs. TRIM21 overexpression reversed the effect caused by knockdown of ELAVL1. Mechanistically, ELAVL1 upregulated TRIM21 by increasing the stability of TRIM21, which ubiquitinated and degraded HOXD8. ELAVL1 bound to TRIM21, which promoted ubiquitination and degradation of HOXD8, thereby promoting ferroptosis to inhibit osteogenic differentiation of CPT MSCs.

Small extracellular vesicles (sEVs) are considered promising gene-delivery vehicles for the treatment of osteoarthritis (OA). This study aimed to explore the molecular mechanism by which M2 macrophage-derived sEVs (M2-sEVs) modulate chondrocyte proliferation and apoptosis, thereby affecting OA progression. M2 macrophages were successfully induced, and M2-sEVs were successfully isolated. The sEVs were small vesicles with diameters ranging from 50 to 150nm. The exosomal markers, including CD9, CD63, and CD81, were highly expressed, whereas the negative marker calnexin was absent in M2-sEVs. M2-sEVs effectively alleviated OA tissue and chondrocyte damage in both in vivo and in vitro models, evidenced by reduced rat knee joint injury, increased chondrocyte viability, and decreased chondrocyte apoptosis and extracellular matrix (ECM) degradation. Furthermore, M2-sEVs decreased the levels of pro-inflammatory cytokines IL-6 and TNF-α. Osteopontin (OPN) was upregulated within rats with OA and IL-1β-induced chondrocytes. Silencing of OPN exacerbated IL-1β-induced chondrocyte damage and partially abrogated the therapeutic effects of M2-sEVs. Additionally, M2-sEVs enhanced OPN expression and activated CD44 and the PI3K/AKT signaling pathway. In conclusion, M2-sEVs promoted OPN expression to improve knee joint tissue damage in rats with OA and chondrocyte damage. This protective effect of M2-sEVs might be associated with the activation of CD44 and the PI3K/AKT signaling.