Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid accumulation and plaque formation, representing a leading cause of life-threatening cardiovascular events. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been implicated in atherosclerotic progression; however, the exact mechanism remains elusive. Here, we identified cathepsin B (CTSB) as a novel ferroptosis-related gene through bioinformatic screening and investigated its functional role in macrophage-derived foam cells and plaque instability using both in vitro and in vivo models. Mechanistically, CTSB bound to and stabilized nuclear factor erythroid 2-related factor 2 (NRF2), facilitating its nuclear translocation and subsequent transcriptional activation of heme oxygenase-1 (HMOX1), a pivotal regulator of iron homeostasis and oxidative stress. Consequently, CTSB-driven HMOX1 upregulation promoted ferroptosis and exacerbated plaque vulnerability, whereas CTSB knockdown or pharmacological inhibition reversed these effects. Collectively, our findings uncover a CTSB/NRF2/HMOX1 signaling cascade that drives ferroptosis in macrophage-derived foam cells and promotes plaque instability, positioning CTSB as a promising therapeutic target for stabilizing high-risk atherosclerotic plaques.

The introduction of tyrosine kinase inhibitors (TKIs) targeting driver oncogenes such as EGFR, ALK, and KRAS has substantially reshaped the treatment landscape of non-small cell lung cancer (NSCLC) and improved patient outcomes. However, inevitable acquired resistance remains the core obstacle to therapeutic success. Unlike previous studies that have largely focused on secondary mutations or bypass activation, the role of proteostasis imbalance in the evolution of resistance is increasingly recognized. The ubiquitin-proteasome system (UPS), as the central machinery for intracellular protein degradation and quality control, precisely regulates the stability, localization, and function of numerous key proteins, and is extensively involved in cell cycle progression, apoptosis, DNA damage repair, and various signaling pathways. Accumulating evidence indicates that UPS dysregulation is a critical factor in the emergence and maintenance of resistance to targeted therapy in NSCLC. By altering the expression and activity of specific E3 ligases or deubiquitinating enzymes (DUBs), resistant cells can remodel their proteome to achieve aberrant stabilization of pro-survival proteins, degradation of pro-apoptotic factors, or activation of alternative survival pathways, thereby adapting to TKI pressure. In light of this, developing interventions targeting core components of the UPS-such as next-generation proteasome inhibitors, molecular glues, PROTACs, and inhibitors of E3 ligases or DUBs-has emerged as a highly promising direction to overcome resistance. This review aims to systematically summarize the molecular mechanisms by which the UPS contributes to targeted therapy resistance in NSCLC, evaluate recent progress in emerging UPS-targeting strategies-most of which remain at preclinical or early clinical stages-and critically discuss the major barriers impeding their clinical translation, including off-target toxicity, selectivity issues, and the need for rationally designed combination regimens.

HCC (Hepatocellular carcinoma) is one of the malignant tumors with high morbidity and mortality worldwide. Its pathogenesis is complex and the efficacy of existing treatments is limited. Therefore, in-depth exploration of key regulatory molecules and their mechanisms is of great significance for the early diagnosis and targeted therapy of HCC. In this study, HCC cell lines Huh-7 and HepG2 were used as research models to systematically investigate the biological function and molecular regulatory mechanism of FAM117B (family with sequence similarity 117 member B) in HCC progression through gene knockdown and overexpression, cell functional assays, co-immunoprecipitation coupled with mass spectrometry, post-translational modification detection, transcriptome sequencing and nude mouse subcutaneous tumorigenesis assays. High FAM117B expression predicted poor prognosis and positively correlated with pathological grade; functionally, FAM117B exhibited robust oncogenic activity, where its knockdown suppressed proliferation, clonogenicity, invasion, and migration, and its overexpression enhanced these phenotypes. Mechanistic studies revealed that FAM117B directly physically interacted with NAT10 (N-acetyltransferase 10), an acetyltransferase, forming a bidirectional regulatory loop: on the one hand, FAM117B maintained the protein stability of NAT10 by inhibiting its K48-linked ubiquitination and subsequent proteasomal degradation; on the other hand, NAT10, as a key acetyltransferase, specifically mediated the acetylation of FAM117B at lysine 429, providing a molecular basis for the functional role of FAM117B. Transcriptome sequencing and molecular verification demonstrated that the FAM117B/NAT10 axis targeted and regulated JAK2 (Janus kinase 2) expression, activated the downstream JAK-STAT3 (signal transducer and activator of transcription 3) signaling pathway, and thereby drove the malignant biological behaviors of HCC cells. In vivo, dual knockdown of FAM117B and NAT10 significantly reduced xenograft growth, decreased Ki67, and increased apoptosis; notably, NAT10 depletion abrogated the tumor-promoting effects of FAM117B overexpression. In conclusion, this study reveals the molecular mechanism by which FAM117B promotes HCC progression via forming a bidirectional regulatory loop with NAT10 and activating the JAK-STAT3 signaling pathway through acetylation modification, providing a novel potential target and theoretical basis for targeted therapy of HCC.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by aberrant epigenetic regulation. Although SET domain-containing 5 (SETD5) is structurally classified as a member of the histone methyltransferase family, it lacks canonical methyltransferase activity and functions primarily through nonenzymatic mechanisms. While recognized as a modulator in normal hematopoiesis, the role of SETD5 in T-ALL remains undefined. Here, we show that SETD5 contributes to efficient T-ALL initiation and progression in the models examined. Using ICN1-driven murine T-ALL models (Vav-Cre;Setd5[fl/fl] and Mx1-Cre;Setd5[fl/fl]), we show that genetic ablation of Setd5 impairs efficient leukemia initiation. In transplantation assays, Setd5 depletion reduces leukemia burden, prolongs survival, and impairs leukemic infiltration into the spleen, liver, and thymus. Mechanistically, transcriptomic profiling of Setd5-deficient CD3[+] T-ALL cells reveals selective repression of transcriptional programs governing cell migration, motility, and cytoskeletal organization. Key regulators of actin cytoskeleton remodeling and extracellular matrix interaction-including Plxnb2, Mmp14, Ceacam1, and Clstn1-are among the most downregulated genes, as validated by RT-qPCR. Furthermore, SETD5 knockdown in human T-ALL cell lines Jurkat and MOLT-4 cells result in a marked reduction in proliferation and migration. Our findings demonstrate that SETD5 contributes to T-ALL progression by regulating transcriptional programs that contribute to leukemic cell migration and infiltration, suggesting that SETD5-associated transcriptional programs warrant further investigation as potential vulnerabilities in T-ALL.

Chromosomal instability (CIN) drives clear cell renal cell carcinoma (ccRCC) progression, yet its upstream triggers remain elusive. To identify key drivers governing renal genomic integrity, we integrated machine learning-driven screening with Mendelian randomization analysis to prioritize candidates associated with both CIN and clinical outcomes. This computational pipeline identified Polycystic Kidney and Hepatic Disease 1 (PKHD1) as a top candidate and a crucial guardian of the renal genome. Through single-cell and spatial transcriptomics, combined with functional assays in ccRCC cell lines and clinical cohort validation, we characterized the expression dynamics and biological function of PKHD1. Mechanistically, PKHD1 localizes to the centrosome, where it maintains the CEP97-CP110 complex. Depletion of PKHD1 leads to the loss of CP110 at the centrosome, thereby triggering both CIN and epithelial-to-mesenchymal transition (EMT). We further demonstrate that PKHD1 is silenced in ccRCC through the epigenetic inactivation of a distal 800-kb enhancer, which physically interacts with the PKHD1 gene within a shared topologically associating domain (TAD). Collectively, this study establishes a novel link between 3D genomic regulation and centrosome homeostasis, identifying the loss of the PKHD1-CEP97-CP110 axis as a pivotal event in kidney cancer progression and a potential biomarker for aggressive disease.

Osteosarcoma progression cannot be fully explained by tumor-intrinsic genetic alterations alone; it is shaped by continuous interactions with the bone microenvironment. Emerging evidence indicates that osteosarcoma cells actively sense, appropriate, and remodel bone-specific structural, metabolic, and immune programs, establishing a self-reinforcing niche that supports tumor growth, immune evasion, and therapeutic resistance. We integrate multi-level mechanistic insights into a unified conceptual framework-the bone-specific vicious cycle-which conceptualizes osteosarcoma evolution as a staged process encompassing niche initiation, amplification, and stabilization. Mechanical signals derived from the rigid bone matrix, calcium-driven proliferative circuits, osteoclast-mediated bone destruction, metabolic immunosuppression, and extracellular matrix remodeling are proposed to collectively drive the remodeling of the physiological bone niche toward an immune-excluded, tumor-supportive state. This stabilized cycle not only sustains malignant progression but also underlies both primary and acquired resistance to conventional and immunologically based therapies. By integrating cellular, metabolic, and immunological dimensions, this framework highlights actionable nodes for intervention and indicates that disrupting niche-level feedback loops is a prerequisite for restoring therapeutic sensitivity in osteosarcoma. Reframing osteosarcoma as an ecological disease provides a rationale for combination strategies targeting both tumor cells and the bone microenvironment.

Vitiligo is a common acquired depigmentation disorder affecting approximately 0.5-2% of the global population, characterized by the selective destruction of melanocytes leading to white patches on the skin. The pathogenesis of vitiligo involves complex interactions between genetic susceptibility, autoimmune responses, oxidative stress, and melanocyte dysfunction. Recent studies have demonstrated that ferroptosis, a novel iron-dependent form of programmed cell death, may play a critical role in melanocyte loss in vitiligo. Ferroptosis is characterized by iron accumulation, lipid peroxidation, glutathione (GSH) depletion, and decreased glutathione peroxidase 4 (GPX4) activity. This form of cell death differs fundamentally from apoptosis, necrosis, and autophagy in its morphological, biochemical, and genetic characteristics. Understanding the role of ferroptosis in vitiligo pathogenesis opens new avenues for therapeutic intervention and may explain why melanocytes in vitiligo patients are particularly vulnerable to oxidative damage. Multiple experimental and clinical studies have now confirmed the upregulation of ferroptosis biomarkers including transferrin receptor 1 (TFR1), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) in vitiligo lesions, alongside downregulation of GPX4 and the cystine/glutamate antiporter System Xc-. Emerging evidence further implicates epigenetic regulators such as SIRT7 and RNA-binding proteins such as SLC3A2 in modulating melanocyte ferroptosis susceptibility. This comprehensive review systematically summarizes current knowledge on ferroptosis mechanisms in vitiligo, including the System Xc-/GPX4 axis, iron metabolism dysregulation, lipid peroxidation pathways, and their interactions with autoimmune responses. We also explore emerging therapeutic strategies targeting ferroptosis-related pathways, including iron chelation, GPX4 enhancement, lipid peroxidation inhibitors, NRF2 activators, and natural compounds such as baicalein. By integrating basic research findings with clinical observations, this review provides novel insights into vitiligo pathogenesis and establishes a theoretical foundation for developing innovative treatment strategies based on ferroptosis regulation. Crucially, by contrasting the ferroptosis-hypersensitive profile of vitiligo melanocytes with the ferroptosis-resistant molecular landscape of melanoma cells, this review proposes a novel framework for melanocyte-lineage-selective ferroptosis modulation as a therapeutic strategy.

A deficiency of fatty acid oxidation (FAO) is the key hallmark in renal tubular epithelial cells (TECs) under high-altitude hypoxia (HH), reflecting their physiological reliance on FAO as a major energy source. The resulting lipid accumulation is likely to promote lipotoxicity-induced pathological injury in renal tissue. However, the molecular mechanisms underlying HH-induced renal lipotoxic injury remain poorly understood. This study identifies hepatocyte nuclear factor 4α (HNF4α) as a key regulator of lipid metabolism. HNF4α expression in kidney tissues was significantly downregulated after HH exposure. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that HNF4α directly binds to and regulates the transcription of the Acyl-CoA Oxidase 1 (ACOX1), a key gene involved in FAO, in the kidney of hypoxia-exposed rats. Further functional studies indicated that lentivirus-mediated overexpression of HNF4α significantly alleviated hypoxia-induced lipid accumulation and the decrease in adenosine triphosphate (ATP) production, while effectively inhibiting cell apoptosis. In contrast, knockdown of HNF4α markedly aggravated cellular lipotoxicity, as evidenced by increased intracellular lipid accumulation, reduced ATP levels, and enhanced apoptosis. Mechanistically, HNF4α directly activates ACOX1 transcription and modulates Carnitine Palmitoyltransferase1A (CPT1A) expression, thereby enhancing FAO capacity. This leads to reduced reactive oxygen species (ROS) accumulation, improved mitochondrial membrane potential, and promoted ATP synthesis, ultimately mitigating hypoxia-related cellular injury. Overall, our findings uncover a previously unrecognized role for HNF4α in maintaining lipid homeostasis in TECs under hypoxic conditions and provide novel mechanism and target for HH-associated kidney injury.

Elucidating the complex molecular drivers of non-small cell lung cancer (NSCLC) and identifying novel therapeutic targets are urgently needed. Although circPRKCA is implicated in tumorigenesis, its role in NSCLC remains poorly characterized. This study investigates the biological functions and regulatory mechanisms of circPRKCA in NSCLC. CircPRKCA expression and downstream target expression were assessed via qRT-PCR and Western blotting. In vitro functional assays evaluated circPRKCA's role in NSCLC cells. Regulatory mechanisms were further examined using database analysis, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays. In vivo tumor growth was evaluated in mouse xenograft models. CircPRKCA was significantly upregulated in NSCLC and promoted tumor growth and metastasis. Our data suggest that circPRKCA may act as a scaffold for RNA-binding proteins (RBPs), potentially facilitating the recruitment of SRSF1 to HIF-1A mRNA, which appeared to correlate with increased HIF-1A stability. HIF-1A overexpression enhanced NSCLC cell proliferation via PKM2-mediated glycolysis. High circPRKCA expression correlated with poor survival in NSCLC patients. CircPRKCA-SRSF1 axis enhanced proliferation and suppressed apoptosis by stabilizing HIF-1A and modulating PKM2-driven glycolysis. These findings reveal novel diagnostic biomarkers and therapeutic strategies for NSCLC.

The fat mass and obesity-associated protein (FTO), the first identified N6-methyladenosine (m6A) RNA demethylase, has become both a leading candidate target in oncology and one of its most contested, behaving as an oncogene in some malignancies and as a tumor suppressor in others. Multiple inhibitor classes, FB23 derivatives, proteolysis-targeting chimera (PROTAC) degraders, repurposed entacapone, and tumor-targeted nanomedicines, have entered preclinical development, yet the clinical proposition remains unresolved because no framework currently predicts directionality or matches strategy to patient. We argue that this impasse reflects a missing conceptual frame, not missing molecules. Reading the field through a three-layer regulatory code offers a way to organize this paradox: an input code, in which K88 acetylation, USP7/USP30-mediated deubiquitination, oncometabolite 2-hydroxyglutarate, microbial CagA, lineage-specific transcription factors, and non-coding RNA scaffolds set FTO state; a processing code, in which subcellular localization, including localization to membraneless compartments, the YTHDF2 versus IGF2BP reader dichotomy, and a proposed non-catalytic scaffolding role select substrate fate; and an output code that maps onto metabolic rewiring, ferroptotic and pyroptotic decisions, immune sculpting, therapy resistance, and exosomal microenvironmental reach. The framework reorganizes therapeutic logic, direct inhibition, indirect modulation, rational combinations, or pharmacological activation, and reframes FTO from a contested target to a context-aware one whose translation depends on direction-aware precision oncology. Because the input, processing, and output layers are frequently drawn from different experimental systems, we present this code as an interpretive and hypothesis-generating scaffold rather than a validated predictive tool: it clarifies why FTO directionality varies and defines what must be measured to anticipate it, while prospective, within-model testing is still required before directionality can be assigned, or therapy matched, in an individual tumor.

Acute pancreatitis (AP) is a digestive system disorder characterized by overactivation of pancreatic enzymes within the pancreas, leading to severe pathological features. M1 macrophage activation and subsequent pro-inflammatory responses are essential in AP development. Investigating macrophage polarization during AP can help further elucidate the pathogenesis of AP and provide theoretical foundations and therapeutic strategies for AP. In this study, we found that FCER1G expression and Notch1 activity were up-regulated in LPS-induced M1 macrophages. FCER1G and Notch1 knockdown could inhibit LPS-induced inflammation in M1 macrophages and pancreatic acinar cell (PAC) damage, indicating the vital functions of FCER1G and Notch1 in M1 macrophage polarization. Further research indicated that FCER1G promotes M1 macrophage polarization and PAC damage by regulating, rather than enhancing, interactions with Notch1 in LPS-induced M1 macrophages. Finally, we showed that inhibition of FCER1G could alleviate AP injury through the Notch1 pathway in mice, providing a novel intervention target for AP therapy.

Solid tumors evade adaptive immunity through MHC class I downregulation, stromal barricades, and T-cell exhaustion, rendering conventional immunotherapies ineffective in "cold" lesions. This review introduces the Innate Regenerome, a unified framework harnessing mesenchymal stromal cells (MSCs), CAR-engineered natural killer (CAR-NK) cells, and CAR-macrophages (CAR-M) to simultaneously eliminate malignancy and restore tissue architecture. MSCs serve as switchable niche engineers, delivering logic-gated anti-fibrotic and chemotactic cues. CAR-NK cells provide rapid, non-exhaustible cytotoxicity with favorable safety and metabolic flexibility for hypoxic tumors. CAR-M function as phagocytic engines and antigen-presenting factories, converting engulfed debris into adaptive immunity. We propose a tripartite circuit where MSCs scaffold the niche, CAR-NK cells generate immunogenic stress, and CAR-M complete clearance and cross-presentation. Emerging strategies include EV-mediated coordination, synNotch spatial gating, and in vivo mRNA-LNP programming. Translational priorities comprise humanized MISTRG6 models, organoid-on-chip platforms, and response endpoints beyond RECIST. The Innate Regenerome repositions innate immunity from auxiliary force to central architect of antitumor and regenerative therapy.