Mechanical forces are fundamental drivers of morphogenesis, yet the molecular mechanisms that convert these physical cues into transcriptional responses remain incompletely understood. This review synthesizes current evidence identifying the mechanosensitive ion channel Piezo1 as a master regulator of developmental processes. The structural and biophysical principles underlying Piezo1 function are highlighted, focusing on its trimeric architecture and force-from-lipids gating mechanism that directly couples membrane tension to Ca2+ influx. Its spatiotemporal expression during embryogenesis is reviewed, and the downstream pathways it activates are examined, including mitogen-activated protein kinase (MAPK) and yes-associated protein/transcriptional co-activator with PDZ-binding moti (YAP/TAZ), alongside crucial crosstalk with canonical morphogen signaling cascades such as Notch, Wntwingless/integrated signaling pathway (Wnt)/beta-catenin (β-catenin), and bone morphogenetic protein/transforming growth factor-beta (BMP/TGF-β). Functional studies across diverse model systems demonstrate that Piezo1 orchestrates conserved morphogenetic events, including vascular and lymphatic patterning, neurogenesis, epithelial morphogenesis, myoblast fusion, and osteogenesis. Human genetic data further underscore its nonredundant role, linking gain-of-function mutations to dehydrated hereditary stomatocytosis and loss-of-function mutations to primary lymphatic dysplasia. Collectively, these findings establish Piezo1 as an essential integrator of mechanical and biochemical signals, central to tissue patterning and organ formation. The review concludes by emphasizing Piezo1's therapeutic potential in regenerative medicine and developmental disorders, while also underscoring the challenges of targeting such a broadly influential mechanosensor.

This study aimed to assess the association between fat mass and obesity-associated ( FTO ) genetic variants and colorectal cancer (CRC) risk in a retrospective case–control cohort. FTO expression in CRC versus normal tissues was analyzed via UALCAN (TCGA), and the regulatory effects of rs9930506 and rs9940128 were assessed using GTEx data. A retrospective analysis was conducted on 870 CRC cases and 870 matched controls. Genotyping was performed using PCR-RFLP. Association with CRC risk was assessed by unconditional logistic regression with odds ratio ( OR ) and 95% confidence interval ( CI ), adjusted for age, sex, smoking status, and drinking status. Bioinformatics analysis revealed elevated FTO expression in colon cancer ( p = 0.043), but not in rectal cancer ( p = 0.250). Its variants rs9930506 and rs9940128 showed regulatory effects on gene expression in skeletal muscle and esophagogastric junction ( p < 0.001). The FTO variant rs9930506 A > G was significantly associated with reduced CRC risk across multiple genetic models (GG vs. AA: OR = 0.30, 95% CI = 0.16–0.56, p < 0.001; AG+GG vs. AA: OR = 0.76, 95% CI = 0.62–0.93, p = 0.007; GG vs. AG+AA: OR = 0.32, 95% CI = 0.17–0.59, p < 0.001). These protective associations were preserved in non-smokers (all p < 0.05) and non-drinkers (all p < 0.01). In contrast, rs9940128 showed no significant association with CRC risk in any genetic model or stratum (all p > 0.05). The FTO rs9930506 polymorphism is associated with reduced CRC risk in this population, suggesting its role as a potential susceptibility marker.

The ubiquitin-proteasome system (UPS) is a crucial determinant of protein stability and activity in various aspects of physiological function and disease development. The well-characterized class of regulatory enzymes within the UPS is deubiquitinating enzymes (DUBs), and their effects, particularly those of the ubiquitin-specific proteases (USPs), oppose ubiquitination. All DUB activities can be more or less disrupted in various cancers, including breast cancer, and DUB alterations contribute substantially to tumor initiation, progression, and many forms of therapeutic resistance. In this review, we discuss the various molecular mechanisms of action of USPs on breast cancer hallmarks, including proliferation, aggression or metastasis, evasion of apoptosis, immune evasion, and metabolic programming. We evaluate how specific USPs stabilize oncogene members by deubiquitinating target proteins or deubiquitinating tumor suppressors, thereby influencing a variety of cellular behaviors, from regulating the cell cycle to modulating immune responses. Due to their important role in breast cancer pathology, the alterations of USP activities and the functional roles of selective USPs will also demonstrate some ways USPs present promising therapeutic targets in breast cancer. We will provide a comprehensive overview of USP inhibitors to date, focusing on their utilization in developing and describing efficacy in breast cancer models. Pharmacological inhibitors of specific USPs, such as pimozide, trifluoperazine, rottlerin, 6-thioguanine, and costunolide, are highlighted for their potential to inhibit proliferation, metastasis, induce apoptosis, and circumvent therapy resistance across breast cancer subtypes (triple-negative and HER-2 positive). The review highlights the complex and often contradictory roles of USPs in breast cancer and points to the immense promise of targeting these enzymes to develop new and efficacious anticancer therapies.

Idiopathic pulmonary fibrosis (IPF) arises from interactions between genetic predisposition and environmental exposures (exposome). This study used an integrative multi-omics to identify co-regulated genes in IPF fibroblasts. Differentially expressed miRNAs (DEMis) in lung fibroblasts from eight patients with IPF and four controls were defined by the threshold number of misclassifications <0.05, p < 0.05, fold change >1.2, and analyzed with DNA methylation (GSE107226) and mRNA expression datasets (GSE71351), respectively. miRNA–mRNA networks were constructed and analyzed for functional enrichment. Exposome-associated genes were identified through PubMed reviews. Five DEMis ( miR-143-3p , miR-138-5p , miR-152 , miR-181a-5p , miR-181b-5p ) showed significant negative correlations with 43 differentially expressed genes (DEGs; p < 0.05). A network map visualized interactions between these 5 DEMis and their 43 target DEGs, highlighting strong miRNA–mRNA relationships. Integrative analysis of DNA methylation data identified 65 epigenetically regulated DEGs and 113 non-epigenetically regulated DEGs. Epigenetically regulated DEGs were enriched in cell motility, tissue development, and intercellular communication. Among 12 hub genes, S100A4 , PTGS2 , FGF7 , LEF1 , and TFPI were identified as potentially responsive to environmental risk factors such as cigarette smoke and particulate matter. This study demonstrates that coordinated regulation by miRNAs and DNA methylation modulates fibroblast gene expression in IPF, uncovering exposome-responsive pathways and potential therapeutic targets.

N6-methyladenosine (m6A) methylation, the most prevalent internal mRNA modification in eukaryotes, plays a crucial role in regulating various biological processes. Recent advancements reveal its significant involvement in osteoarthritis (OA) and intervertebral disc degeneration (IVDD). m6A modifications influence key cellular processes such as inflammation, stress responses, and matrix homeostasis, which are pivotal in OA and IVDD pathogenesis. In OA, m6A methylation affects inflammatory responses, macrophage polarization, and chondrocyte ferroptosis, while in IVDD, it regulates RNA methylation and matrix integrity. Additionally, m6A interacts with noncoding RNAs, impacting their stability and function, thus influencing disease outcomes. Emerging evidence suggests that targeting m6A pathways could provide novel therapeutic strategies for managing OA and IVDD. Further research into m6A’s role in these diseases may reveal new biomarkers and therapeutic targets, offering potential for more effective treatments and improved patient outcomes.

The long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL) expression is upregulated in hepatocellular carcinoma (HCC) tissues, and decreased ANRIL expression inhibits cell proliferation, metastasis, and invasion and induces apoptosis in HCC cells. However, the molecular mechanism by which ANRIL is involved in HCC tumorigenesis is unclear. In this study, ANRIL was found to be a significantly upregulated lncRNA in HCC and was associated with the metastasis and poor prognosis of HCC. p53 plays an important role in the mechanism of carcinogenesis. Therefore, we hypothesized that ANRIL plays a biological role by regulating the p53 signaling pathway. To comprehensively evaluate the biological function of ANRIL, bioinformatics analysis, quantitative real-time polymerase chain reaction, Western blotting, wound healing, Transwell, cell colonization assay, cell counting kit-8, reactive oxygen species, JC-1, EdU, and terminal deoxynucleotidyl transferase-mediated dUTP Nick end labeling were performed. The results showed that the knockdown of ANRIL inhibited HCC cell viability, colony forming ability, functions such as metastasis and invasion, and epithelial-mesenchymal transition. Meanwhile, the knockdown of ANRIL also resulted in the decreased expression of the p53 protein. All these effects are tightly intertwined with the regulation of the p53 signaling pathway. Thus, ANRIL may contribute to the development of new drugs for the treatment of human HCC.

Ferroptosis plays a crucial role in regulating tumor growth and represents a promising therapeutic target for nonsmall cell lung cancer (NSCLC). RNA-binding protein with serine-rich domain 1 (RNPS1) has been closely associated with the development of various cancer types, but its role in NSCLC remains unclear. In this study, we used lentiviral vectors to silence or overexpress RNPS1 in NSCLC cells and then assessed cell proliferation along with ferroptosis markers, such as lipid reactive oxygen species (ROS). Bioinformatics analysis revealed that RNPS1 was upregulated in clinical NSCLC samples. Consistently, functional experiments showed that overexpression of RNPS1 promoted cell proliferation, while RNPS1 knockdown inhibited cell proliferation. Furthermore, RNPS1 overexpression attenuated erastin-triggered ferroptosis by suppressing the accumulation of lipid ROS and malondialdehyde, as well as by preventing the depletion of glutathione. Mechanistic investigations identified that RNPS1 stabilized ETS variant transcription factor 4 (ETV4) mRNA. Importantly, blocking ETV4 expression partially reversed RNPS1 overexpression-mediated suppression of ferroptosis. Collectively, these results support the notion that RNPS1 acts as a novel suppressor of ferroptosis in NSCLC progression.

Arrestin beta 1 (ARRB1) and ARRB2, which are multifunctional adapters in G protein-coupled receptor signaling, are highly involved in liver-related diseases. ARRB1 plays a protective role against ischemia-reperfusion injury, acute liver injury, and nonalcoholic fatty liver disease by inhibiting apoptosis and improving metabolic disorders. ARRB1 has been reported to be protective in mouse liver fibrosis models; however, it has also been shown to have pathogenic effects in human liver fibrosis. This discrepancy may be due to limitations in mouse models and species differences. In contrast, ARRB2 has dual functions in liver-related diseases. On the contrary, it reduces acute hepatitis and ischemic injury by inhibiting the NF-κB/c-Jun N-terminal kinase pathway. On the contrary, it accelerates disease progression by activating macrophages and promoting oxidative stress and collagen deposition in autoimmune hepatitis, alcoholic steatohepatitis, and fibrosis. Furthermore, the structural differences between ARRB1 and ARRB2 may determine their signal bias through nuclear output capability, nuclear input capability, and phosphorylation. In-depth analysis of the interaction between ARRBs and their signaling mechanisms is expected to provide accurate therapeutic targets for liver disease.

Gastric cancer is one of the leading causes of cancer mortality worldwide, but the underlying molecular mechanisms by which gastric cancer progresses are not fully understood. While deubiquitinases have emerged as promising therapeutic targets in various cancers, a suitable target deubiquitinase for the treatment of gastric cancer has not yet been identified. Using bioinformatics analyses, we identified that upregulation of ubiquitin-specific peptidase 26 (USP26) was associated with poor patient survival in patients with gastric cancer; moreover, depletion of endogenous USP26 with short hairpin RNAs significantly suppressed the aerobic glycolysis and proliferation in tumor cells. In mechanism, USP26 was revealed to interact with and stabilize c-Myc, which is a key driver of tumor metabolism and carcinogenesis, via suppressing its polyubiquitination and degradation. In summary, these findings suggest that USP26 plays a novel oncogenic role of USP26 by forming a USP26-c-Myc regulatory axis, and that targeting USP26 may be a potential therapeutic strategy for gastric cancer.

Copper plays an essential role in numerous biological functions, requiring tight regulation to prevent toxicity and health complications. Cuproptosis is a recently discovered form of regulated cell death that occurs due to intracellular copper accumulation, with a unique mechanism distinct from other known cell death pathways. It is initiated when copper binds to lipoylated enzymes within the tricarboxylic acid (TCA) cycle, leading to enzyme aggregation, proteotoxic stress, and, ultimately, cell death. Since its identification, cuproptosis has drawn significant attention for its potential application in cancer therapy. Copper-based treatments have shown promise in suppressing tumor growth and may offer therapeutic strategies for tumors resistant to conventional chemotherapy. This article explores the underlying mechanisms of cuproptosis and the involvement of copper in various malignancies, aiming to advance targeted cancer therapies and inspire the development of novel anticancer agents that harness this pathway. Finally, important concepts of cuproptosis and issues to focus on in future studies are discussed.