As chimeric antigen receptor (CAR)-T cell therapy has expanded rapidly to meet the growing global cancer burden; many challenges have emerged as a critical factor influencing its efficacy. However, due to the complicated mechanisms of CAR-T cells, human interference alone was insufficient to optimize the outcomes. In parallel, artificial intelligence (AI) has begun to intersect with CAR-T cells, offering novel computational interferences that can refine therapeutic mechanisms. The literature is still lacking a comprehensive investigation that merges CAR-T cell mechanistic biology and limitations with the advancing abilities of AI to meet these barriers. This review provides an overview of the mechanistic foundations of CAR-T cell. It also investigates the various challenges facing the current CAR-T therapies including toxicity, resistance, and accessibility issues. On this basis, we examined the way AI-based innovations are being utilized to optimize the CAR-T engineering and clinical management. Finally, we examined clinical studies and case studies incorporating AI elements, emphasizing both therapeutic mechanisms and outcomes of the study. By integrating mechanistic biology with computational innovation, this review provides a unified unique perspective that can guide the development of safer and more effective CAR-T therapies.

Liver cancer ranks the second leading cause of cancer-related mortality globally, with a 5-year overall survival rate of about 14.0%. And hepatocellular carcinoma (HCC) constitutes about 80% of it. Given that HCC often remains asymptomatic in its early stages, the diagnosis of the majority of patients occurs at the intermediate or advanced stages, leading to the missed opportunity for surgical resection. Furthermore, the incidence of recurrence after surgical resection for early-stage HCC patients can be as high as 70%. In this context, systemic therapies, including targeted therapies and immunotherapies, have emerged as essential therapeutic strategies for advanced HCC. However, resistance and adverse effects limit their efficacy. This review provides an overview of the molecular signaling pathways underlying HCC and potential mechanisms underlying resistance to systemic therapies and discusses potential therapeutic targets within these pathways. We also examine the clinical outcomes of these systemic therapies, highlighting their efficacy, safety profiles, and the challenges of resistance and toxicity. Finally, we outline future directions for HCC treatment, including combination therapies and personalized treatment strategies, which may offer improved treatment outcomes for individuals with HCC.

Pyroptosis is a special form of cell death that often occurs during excessive inflammation and injury, leading to tissue damage, disease progression, and other related issues. The Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an important regulatory factor in cellular pyroptosis that promotes the inflammatory response. Inhibitors targeting the NLRP3 inflammasome have emerged as promising potential therapeutic agents for inflammatory diseases. Through large-scale screening, we found that the FDA-approved drug CeeNU strongly inhibited NLRP3-mediated pyroptosis. CeeNU exhibited dose-dependent suppression of NLRP3 inflammasome activation and effectively mitigated inflammasome-driven pyroptotic cell death in both human and murine macrophages/microglia. Mechanistically, we further demonstrated that CeeNU specifically binds to arginine 335 within the NACHT domain of NLRP3, abrogating NLRP3 inflammasome activation by blocking its assembly. Importantly, CeeNU showed remarkable protective effects in multiple mouse models of NLRP3 inflammasome-mediated diseases, including experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG), lipopolysaccharide (LPS)-induced septic shock, monosodium urate (MSU)-induced peritonitis, and MSU-induced gouty arthritis. Our results demonstrate that CeeNU, a clinically available drug, acts as an NLRP3 inhibitor and holds therapeutic potential for NLRP3 inflammasome-mediated pyroptotic diseases.

Messenger RNA-lipid nanoparticles (mRNA-LNPs) serve as a revolutionary platform, enabling precise and transient protein expression for both in vivo and in vitro cell engineering without genomic integration. Recent breakthroughs in mRNA design and LNP formulation have expanded their applications across immunotherapy, regenerative medicine, and genome editing. However, challenges such as off-target delivery, immunogenicity, and inadequate organ-specific targeting limit their broader therapeutic utility. This review systematically elaborates the design principles of mRNA-LNPs, including mRNA structural elements and functional lipid components that facilitate endosomal escape. It summarizes recent advances in their applications for cell engineering, both ex vivo and in vivo. Key challenges related to delivery precision and immunogenicity are thoroughly analyzed, alongside strategies to improve targeting through administration routes, surface modifications, and endogenous targeting mechanisms. The article also outlines main directions for developing next-generation mRNA-LNPs. Overall, this review will support further research on mRNA-LNPs and promote their clinical translation in the field of cell engineering.

Isocitrate dehydrogenase (IDH) mutations represent pivotal oncogenic drivers across multiple malignancies. Mutant IDH enzymes acquire neomorphic activity that produces the oncometabolite D-2-hydroxyglutarate (D-2HG), which competitively inhibits α-ketoglutarate-dependent dioxygenases and promotes epigenetic reprogramming, differentiation arrest, and malignant transformation. Beyond tumor cell–intrinsic effects, D-2HG profoundly remodels the tumor immune microenvironment by directly suppressing T-cell proliferation and effector functions, silencing natural killer (NK) cell-activating ligands, and impairing dendritic cell maturation. In this review, we delineate the mechanistic basis of mutant IDH in oncogenesis and evaluate the development of selective allosteric inhibitors validated through rigorous preclinical models demonstrating potent D-2HG suppression. Clinical translation has yielded multiple FDA-approved IDH inhibitors demonstrating significant therapeutic efficacy across diverse IDH-mutant malignancies. Notably, dual inhibitors have extended progression-free survival in gliomas, whereas triple-combination regimens have achieved substantial complete remission rates in acute myeloid leukemia. However, therapeutic resistance has emerged through second-site mutations, clonal evolution, and metabolic reprogramming. We also discuss rational combinatorial strategies integrating IDH inhibitors with hypomethylating agents (HMAs), targeted therapies, and immunomodulatory approaches, alongside emerging technologies such as single-cell profiling and spatial transcriptomics. By addressing both achievements and challenges, this review underscores the translational relevance of IDH-targeted therapy and its potential to reshape precision oncology through refined patient stratification and enhanced therapeutic efficacy.

RNA modification has been established as a pivotal field in epitranscriptomics, representing an emerging, dynamic, and precise regulatory layer in gene expression control. N6-methyladenosine (m⁶A), the most prevalent internal RNA modification, is critical for post-transcriptional regulation of RNA stability, translation, and degradation. In addition to m⁶A, RNA contains a number of other modifications that play important regulatory roles in RNA metabolism, transport, translation, and stability. Our review uses N4-acetylcytidine (ac4C) modification as a research paradigm to conduct a systematic review of the RNA modification research framework. This article begins with RNA modifications, then discusses several RNA modification-related regulatory enzymes before using ac4C as a detailed research example. Starting with the fundamental functions of ac4C in RNA modifications, it discusses its discovery history, the specific mechanisms of the key acetyltransferase N-acetyltransferase 10 (NAT10) in various RNA modifications, existing detection technologies, and the functional significance of ac4C modification under physiological and pathological conditions. This review systematically explains the multidimensional roles of RNA modifications, represented by ac4C, in health and disease. We point out that RNA modification-related regulatory enzymes, such as NAT10, can serve as prognostic biomarkers and therapeutic targets, thereby advancing disease mechanism research and improving clinical diagnosis and treatment.

While adjuvant immunotherapy and BRAF/MEK inhibitors improve the outcomes for BRAF V600-mutant stage III melanoma, comparisons of long-term survival and safety of these therapeutic modalities are currently lacking in Chinese patients. We retrospectively analyzed data from patients with resected stage III BRAF V600-mutant melanoma who received adjuvant therapy between June 2013 and December 2023 across three centers in China. Note that 122 patients were included and categorized into interferon (n = 25), aPD-1 (n = 18), D/T (n = 62), and BRAFi/aPD-1 (n = 17) cohorts. The D/T group demonstrated a significantly longer median RFS compared to the interferon and aPD-1group (22.7 vs. 11.9 months, p = 0.005; vs. 12.5 months, p < 0.001). Similar results were obtained by restricted-mean-survival-time model. Patients who continued D/T beyond 1 year exhibited significantly improved RFS and DMFS compared to those who discontinued at 1 year duration (NR vs. 22.0 months, p = 0.048; NR vs. 22.5 months, p = 0.026). NOTCH4 and IL7R mutations may serve as prognostic and predictive biomarkers for long-term survival and targeted-immunotherapy efficacy, respectively. Adjuvant therapy with D/T may represent the most effective treatment strategy for Chinese patients with stage III melanoma harboring BRAF V600 mutations. A combination of BRAF-targeted therapy and aPD-1 immunotherapy provided comparable efficacy and may be an alternative for a specific patient.

Immunotherapies have transformed the treatment of cancers and infectious diseases by harnessing the precision and adaptability of the immune system. Central to these advances is the major histocompatibility complex (MHC) system, with classical MHC-I molecules well documented for their role in immune surveillance. MHC-dependent therapies, including immune checkpoint blockade (ICB), T cell receptor (TCR)-engineered therapies, and cancer vaccines, have shown substantial clinical promise. However, their broader efficacy is hindered by the extreme polymorphism of classical MHC-I molecules, susceptibility to immune evasion, and frequent downregulation in many disease settings. In contrast, nonclassical MHC-I molecules, including HLA-E, HLA-F, HLA-G, CD1, and MR1, offer alternative therapeutic opportunities. Shaped by strong evolutionary conservation, these molecules exhibit limited polymorphism, specialized antigen repertoires, distinct trafficking behaviors, and the capability to engage both innate and adaptive immune cells. In this review, we synthesize current knowledge of the structural biology, antigen presentation pathways, receptor interactions, and immunoregulatory functions of nonclassical MHC-I molecules. We further highlight emerging therapeutic strategies, including immune checkpoint modulation, cargo-based ligands, conformation-specific biologics, vaccines, and cellular therapies, while critically evaluating translational challenges. By linking specialized structural and functional features to therapeutic design, this review provides a unified framework for exploiting nonclassical MHC-I molecules as next-generation targets in immunotherapy.

Innate lymphoid cells (ILCs) are tissue-resident immune sentinels that play pivotal roles in maintaining tissue homeostasis, orchestrating immune responses, and modulating metabolic balance. They rapidly respond to environmental cues and interplay with other immune cells, thereby mediating host defense and facilitating tissue repair. However, dysregulation of ILC responses is increasingly implicated in the pathogenesis of a broad spectrum of diseases. This review provides a comprehensive overview of ILC biology, beginning with their classification, plasticity, and homeostatic functions. We then dissect the complex, dual roles of ILCs across various pathological conditions. Using sepsis as a paradigmatic example of immune dysregulation, we illustrate how ILCs orchestrate both protective immunity and pathological role in a context-dependent manner. Furthermore, we extend the discussion to cancer, chronic inflammatory diseases, and metabolic disorders, highlighting the tissue-specific functions of ILC subsets. Finally, we synthesize emerging ILC-targeted therapeutic strategies and future research directions, proposing that a nuanced understanding of ILC biology is essential for developing novel immunotherapies aimed at restoring immune homeostasis in human diseases.

The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has significantly improved the survival in EGFR-mutant lung cancer patients. Our team developed limertinib (ASK120067), a novel third-generation EGFR inhibitor with remarkable antitumor effects, which has been launched in China. Despite initial therapeutic responses, EGFR TKIs-treated patients ultimately experience fatal metastatic recurrence and disease progression. However, the underlying mechanism of driving metastasis remains poorly understood. Here, we aim to investigate the pro-metastatic mechanism following treatment with third-generation EGFR TKIs. Transcriptomics analyses of EGFR TKI-resistant tumor models revealed an aberrant upregulation of S1PR3, which conferred enhanced metastatic potential to lung cancer. S1PR3 inhibition dramatically reduced metastasis in resistant cells, while its overexpression potentiated metastatic abilities in parental cells. Notably, S1PR3 was highly enriched in clinical samples with AZD9291 resistance and correlates with poor prognosis. Mechanistically, we found that S1PR3 upregulated RAC1-GTP expression to activate PAK1, thereby promoting epithelial-mesenchymal transition (EMT) and enhancing metastatic capacity of resistant cells. Further studies identified that the overexpression of fibroblast growth factor receptor 1 (FGFR1) increased S1PR3 expression through signal transducer and activator of transcription 4 (STAT4) to promote the emergence of metastatic-resistant cells. Importantly, targeting S1PR3 or FGFR1 blocks metastasis in EGFR TKI-resistant models.

A substantial proportion of patients with X‑-linked inhibitor of apoptosis (XIAP) deficiency develop severe and treatment‑-refractory Crohn's disease (CD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative option for these patients, its outcomes are suboptimal, with a long‑-term survival rate of only 50%. Therefore, identifying novel therapeutic targets is crucial to bridge this unmet clinical need. Here, we demonstrate that the abundance of tuft cells is reduced in both XIAP-deficient CD patients and Xiap knockout (Xiap^−/−) mice. Mechanistically, XIAP deficiency reduces TLE4 ubiquitination, resulting in elevated TLE4 protein levels and consequent suppression of Wnt/β‑-catenin–ASCL2 signaling, which is critical for secretory lineage differentiation. Tuft cell deficiency may increase susceptibility to microbial dysregulation, thereby promoting intestinal inflammation. Furthermore, we demonstrate that JAK inhibition promotes tuft cell regeneration and ameliorates mucosal inflammation in Xiap^−/− mice. Consistently, in an XIAP‑-deficient CD patient, treatment with a selective JAK1 inhibitor effectively increased tuft cell proportion and alleviated colonic symptoms. In conclusion, our study identifies tuft cell deficiency as a trigger of intestinal pathology in XIAP‑-deficient Crohn's disease and suggests JAK inhibition as a promising therapeutic strategy.

The HIV-1 capsid (CA) is a validated antiviral target that plays critical roles in both the early and late stages of the viral life cycle. Using structure-based strategy, we designed and synthesized a series of phenylalanine derivatives containing a 4-quinazolinone scaffold as novel HIV-1 CA inhibitors. Among them, IC-2i exhibited potent antiviral activity in MT-4 cells against HIV-1 NL4-3 (EC₅₀ = 0.65 ± 0.27 nM) and effectively protected cells from HIV-1 IIIB infection. SPR revealed that IC-2i interacts strongly with CA hexamers (K_D = 2.7 ± 0.5 nM) with an extended residence time and competes with host factors CPSF6 and NUP153, disrupting CA assembly and disassembly. IC-2i retained activity against lenacapavir (LEN)-resistant strains, such as N74D (11-fold shift vs. 20-fold for LEN). Crystallographic analysis revealed that IC-2i binds at the CA NTD–CTD interface and forms hydrogen bonds with Thr107 and Ser41 (NTD–NTD interface). Pharmacological evaluation demonstrated favorable properties, including good plasma stability, low toxicity (SI > 1571), and suitable pharmacokinetics with a prolonged half-life following subcutaneous administration (T_1/2 = 19.9 h). Overall, this study identifies 4-quinazolinone-based phenylalanine derivatives as promising HIV-1 CA inhibitors and highlights IC-2i as a potential long-acting therapeutic candidate for HIV-1 treatment.

Emerging immunotherapy holds promise to achieve treatment-free remission (TFR) for chronic myeloid leukemia (CML) patients, the development of which depends on full understanding of mechanisms driving immune evasion. Our current investigation in a mouse CML model revealed dominant presence of neutrophils during CML progression, accompanied by significant reductions and exhaustion of T cells. In coculture, these BCR–ABL1 expressing neutrophil-like CML cells significantly inhibited T cell proliferation. Gene expression profiling revealed that there was a global activation of both neutrophil markers and related immune suppression genes in these CML cells. Correlative analysis revealed strong correlations between the expression of BCR–ABL1 and immune suppression genes, suggesting a potential regulation of those genes by BCR–ABL1. Importantly, we identified CEBPB as a critical transcription factor that directly regulated the expression of master immune modulators TGFB1 and ARG2 through promoter binding, in both human and mouse CML samples. Therefore, blocking BCR–ABL1, or its downstream C/EBPβ, TGF-β and arginase with inhibitors or shRNAs rescued T cell suppression by neutrophil-like CML cells. Accordingly, combination treatment with targeted therapy using ponatinib and immunotherapy with anti-PD1 antibody not only provides rapid remission, but also delayed relapses after treatment discontinuation, justifying combination treatment for TFR of CML.

Laryngeal transplantation offers a promising avenue for functional restoration following total laryngectomy, yet concerns regarding cancer recurrence and perioperative challenges persist. This pilot study evaluates the preliminary outcomes of a refined surgical technique and postoperative follow-up protocol specifically for cancer patients. Between 2023 and 2024, four patients underwent laryngeal transplantation at West China Hospital, with immunosuppressive therapy, microbial prophylaxis, and postoperative rehabilitation. Over a follow-up period ranging from 10 to 26 months, outcomes were heterogeneous. Two recipients (T4 laryngeal squamous cell carcinoma) achieved excellent functional recovery in swallowing and phonation with sustained rejection-free survival for 20 and 23 months and disease-free survival for 20 and 26 months, respectively, though both remained tracheostoma dependent. One of these survivors is currently undergoing treatment for graft rejection after unilateral cessation of immunosuppressants. The remaining two patients succumbed to severe pneumonia with sepsis and tumor recurrence at 10 and 11 months posttransplant. Functional assessments in surviving cases indicated progressive nerve regeneration, with optimal voice and swallowing outcomes achieved approximately 6–8 months postsurgery. Ultimately, these findings demonstrate the technical feasibility of laryngeal transplantation in a pilot cohort of cancer patients, providing critical data for future protocol refinement.

Liver fibrosis is a common pathological process, leading to the development of end-stage liver diseases. It is triggered by various etiological drivers including viral hepatitis, metabolic-associated steatotic liver disease (MASLD), and cholestasis. Given the substantial impact of liver fibrosis on individuals and its associated mortality rates, effective management of this condition is crucial for improving public health. Despite a growing number of preclinical studies and clinical trials, a systematic synthesis remains lacking. In this review, the molecular panorama of liver fibrogenesis is summarized at first, encompassing etiological drivers of chronic liver injury, key cellular players, core signaling pathways, and extracellular matrix dynamics. Therapeutic interventions in preclinical or clinical stages are systematically classified into two main categories: etiological treatment as the foundational approach and mechanism-based antifibrotic therapies. Emerging and future therapeutic strategies, including those targeting gut–liver axis, gut microbiota, and cell-based therapies, are also addressed along with inherent challenges. Furthermore, future perspectives centered on precision medicine, combination therapies, novel target discovery, and advanced drug delivery systems are emphasized. This review offers a comprehensive overview of the etiologies, diagnostic approaches, pathogenic mechanisms, current development of antifibrotic agents, and prospects for future therapeutic directions of liver fibrosis.

Heart failure (HF) following myocardial infarction remains a leading cause of global morbidity and mortality, necessitating novel therapeutic strategies. Salvianolic acid B (SalB), one of the major active components of Salvia miltiorrhiza Bunge, has been shown to effectively reverse ischemia-induced myocardial infarction and improve cardiac function. Here, we report a novel mechanism by which SalB treats postmyocardial infarction heart failure by promoting cardiomyocyte re-entry into the cell cycle. A novel protein target of SalB, Prohibitin 1 (PHB1), was identified using chemical biology techniques. Experiments involving overexpression and knockdown of PHB1 have demonstrated that SalB promotes cardiomyocyte mitosis by acting on PHB1, which in turn upregulates the phosphorylation level of the Raf-ERK pathway. Molecular dynamics simulations provide a comprehensive explanation for the mechanism by which SalB enhances Raf phosphorylation. The findings reveal that SalB binds to the C-terminal of PHB1/2 heterodimer, inducing a conformational change that enhances Raf-ERK pathway activation via Akt-mediated phosphorylation, thereby promoting cardiomyocyte mitosis. The findings of this study propose a promising new molecular mechanism through which SalB can contribute to the preservation and restoration of cardiac function.

An effective chimeric antigen receptor (CAR)-based immunotherapy depends on both a suitable immune cell platform and a tumor-specific antigen to overcome barriers in solid tumors. Natural killer (NK) cell lines are promising platforms for CAR constructs due to their inherent tumor-killing ability, safety profile, and feasibility for standardized, off-the-shelf therapeutic use. Herein, four human NK cell lines (YT, KHYG1, NKL, and NK92) were retrovirally transduced with an anti-Hsp70 CAR targeting membrane-bound heat shock protein 70 (mHsp70), a tumor-specific antigen with broad expression on many solid tumors, but not normal cells. Computational modeling suggested a strong binding between the CAR and the extracellular domain of mHsp70. Although all NK cell lines exhibited successful CAR integration and surface expression, only NKL and NK92 cells maintained stable CAR expression and long-term viability. The anti-Hsp70 CAR NKL and NK92 cells demonstrated enhanced expression of activation markers and secretion of cytotoxic effector molecules, and robust target-specific killing of mHsp70-positive cancer cells, while sparing mHsp70-negative targets. Our findings validate the therapeutic potential of anti-Hsp70 CAR NK cells and the suitability of NKL and NK92 cells for advancing off-the-shelf CAR NK cell therapies, thereby offering a promising strategy for targeting a broad range of solid tumors expressing mHsp70.

Recent advances in high-throughput sequencing, spatial omics, and integrative multiomics analyses have established reproducibly detectable microbial communities within tumor tissues, leading to the conceptualization of tumors as complex ecosystems encompassing an “intratumoral microbiota.” These microorganisms have increasingly been recognized as contributing to tumorigenesis, progression, and therapeutic response through interactions with the immune system, immunometabolic reprogramming of tissues, chronic inflammation, and genomic instability. Nevertheless, current evidence remains piecemeal and descriptive, with limited systematic consolidation of microbial composition, functional mechanisms, and translation to clinical application, particularly across tumor types and microenvironmental contexts. This review summarizes microbial diversity, tumor-type-specific associations, and multilayered mechanisms including immune modulation, metabolic reprogramming, and signaling rewiring, and discusses emerging applications such as biomarker discovery, prognostic stratification, and microbiome-targeted therapeutics. Special focus is placed on tumor microenvironment, microbiota-derived metabolites, and determinants of immunotherapy responsiveness. Overall, this review underscores the intratumoral microbiota as a dynamic and context-dependent regulatory layer in cancer biology and offers an integrated framework to realize microbiome-informed precision oncology, along with avenues for enhanced patient stratification and personalized therapeutic approaches.

Chronic pain represents a pervasive global health crisis and a leading cause of disability, yet its management remains challenged by the intricate heterogeneity of its underlying mechanisms. Transcending traditional symptom-based paradigms, chronic pain is now recognized as a distinct disease entity driven by multidimensional maladaptive plasticity. In this review, we synthesize the current landscape of chronic pain, bridging macrolevel epidemiological burdens with microlevel pathophysiological insights. We dissect the complex biological networks driving pain chronification, ranging from peripheral sensitization and ion channel dysfunction to central synaptic reorganization, spinal disinhibition, and maladaptive neuro–immune crosstalk involving glial activation and autoantibody-mediated mechanisms. Notably, we highlight emerging frontiers, including sexual dimorphism in immune signaling, metabolic reprogramming, and epigenetic memory. Furthermore, we critically evaluate the evolution of clinical management strategies, integrating pharmacological innovations, advanced neuromodulation, and digital therapeutics. Finally, we address the persistent translational chasm between basic discovery and clinical efficacy, advocating for a paradigm shift from “one-size-fits-all” approaches toward mechanism-based precision medicine—underpinned by robust biomarkers and deep phenotyping—to revolutionize therapeutic outcomes.

Tumor stroma is a critical component of the tumor microenvironment (TME) that plays a pivotal role in cancer progression and therapeutic response. Beyond providing structural support, stromal components actively regulate tumor growth, metastasis, immune evasion, and drug resistance. Tumor stroma consists of both noncellular elements, particularly the extracellular matrix (ECM), and diverse stromal cells such as cancer-associated fibroblasts and mesenchymal stem cells. These components collectively form a dense and dynamic barrier that restricts drug penetration, increases interstitial pressure, and promotes an immunosuppressive microenvironment. Despite growing recognition of the importance of stromal biology, a systematic understanding of stromal-targeted therapeutic strategies and their translational potential remains incomplete. In this review, we comprehensively summarize the biological functions of major stromal components in tumor development and therapy resistance. We further discuss current therapeutic strategies targeting the tumor stroma, including stromal cell depletion, vascular normalization, ECM-modulating approaches, and emerging nanomaterial-based delivery systems designed to enhance drug penetration and therapeutic efficacy. In addition, recent progress in preclinical studies and clinical trials of stromal-targeted therapies is highlighted. By integrating advances in tumor biology, nanomedicine, and translational oncology, this review provides a comprehensive perspective on stroma-targeted cancer therapy and outlines future directions for precision medicine.

Efferocytosis—the phagocytic clearance of apoptotic cells (ACs)—is essential for maintaining tissue homeostasis, immune tolerance, and inflammation resolution. Beyond classic receptor-mediated recognition, this process drives phagocyte metabolic reprogramming to actively facilitate tissue repair. Consequently, defective efferocytosis serves as a core pathogenic mechanism across major human diseases. This review outlines the molecular and metabolic foundations of efferocytosis and defines four universal hallmarks of its dysfunction: senescence-driven impairment, unresolved inflammation, loss of immune tolerance, and fibrotic tissue repair. Subsequent sections explore how these defects manifest in cardiovascular, autoimmune, and neurodegenerative conditions, as well as cancer. Because efferocytosis exhibits a dual pathophysiological nature, therapeutic interventions must be highly disease-specific. Enhancing apoptotic clearance can effectively resolve chronic inflammatory and fibrotic conditions. Conversely, because tumors hijack these same pathways to build immunosuppressive microenvironments, inhibiting efferocytosis remains a critical strategy in oncology. The synthesis of these divergent roles informs a “context-dependent directionality” framework to guide the clinical translation of efferocytosis-targeted precision therapies.

Cardiovascular diseases remain the leading cause of death worldwide. Maladaptive transcriptional programs drive the fibrosis, hypertrophy, and vascular inflammation that characterize these pathologies. Histone posttranslational modifications regulate these programs by remodeling chromatin accessibility and transcriptional output in cardiomyocytes, vascular cells, and immune cells. These modifications include methylation, acetylation, and metabolite-derived acylations. While the enzymatic machinery of classical histone marks is increasingly well defined, the cell-type-specific integration of these regulators into dynamic cardiovascular networks remains incompletely understood. This narrative review summarizes experimental and human studies published up to early 2026. We examine how classical marks such as H3K27me3 and H3K9ac, alongside emerging metabolic sensors like histone lysine lactylation, shape core pathobiological programs, including oxidative stress responses, endothelial dysfunction, and extracellular matrix remodeling, across major cardiovascular syndromes. We further critically evaluate the enzymatic machinery and pharmacological strategies by contrasting broad-spectrum histone deacetylase inhibition with precision approaches, including bromodomain inhibition and locus-selective epigenome editing. Finally, we address translational constraints such as drug delivery and off-target effects. We propose that single-cell resolution and spatial multiomics will be essential to identify compartment-specific targets and advance precision cardiovascular epigenetic therapeutics.