Multidrug-resistant (MDR) bacteria belonging to the ESKAPE group-Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.-represent some of the most urgent threats to global health. These pathogens are major causes of healthcare-associated infections and are characterized by extensive antibiotic resistance, biofilm formation, persistence phenotypes, and multiple virulence mechanisms that limit the effectiveness of conventional antimicrobial therapies. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising non-antibiotic approach based on the light activation of photosensitizers, leading to the generation of reactive oxygen species (ROS) that induce multi-target oxidative damage. This review evaluates the current evidence supporting aPDT against ESKAPE pathogens and examines the biological and therapeutic factors that influence treatment outcomes. Across ESKAPE pathogens, aPDT frequently achieved clinically relevant antibacterial effects, including reductions of ≥3 log₁₀ CFU under optimized conditions. However, treatment efficacy varied substantially according to bacterial envelope architecture, biofilm organization, and infection accessibility. Gram-positive pathogens generally exhibited higher susceptibility, whereas Gram-negative species-particularly P. aeruginosa-required strategies to overcome outer membrane barriers, biofilm-associated protection, and limited photosensitizer penetration. Beyond direct antimicrobial activity, numerous studies reported biofilm disruption, modulation of virulence-associated pathways, and enhanced susceptibility to conventional antibiotics. Collectively, these findings suggest that aPDT efficacy is determined not only by photosensitizer potency but also by pathogen-specific structural and physiological constraints. Current evidence supports aPDT as a promising adjunctive strategy against MDR ESKAPE pathogens, particularly in localized and accessible infections where effective light delivery can be achieved. The therapeutic performance of aPDT appears to follow a pathogen-dependent gradient shaped by bacterial structure, biofilm complexity, and treatment accessibility. These observations support a pathogen-adapted framework for aPDT development, in which photosensitizer selection, delivery systems, and irradiation strategies are tailored to the biological characteristics of individual pathogens. Future progress will require greater protocol standardization, improved translational models, and well-designed clinical studies to facilitate the integration of aPDT into antimicrobial practice.
Cerebral ischemic stroke (CIS) is characterized by high morbidity, disability, and mortality, representing a major global public health challenge and imposing a substantial social and economic burden worldwide. Cerebral ischemia/reperfusion (I/R) triggers complex pathological cascades, resulting in secondary brain injury, thereby limiting the therapeutic efficacy of single-target interventions. Therefore, the development of novel neuroprotective strategies with multitarget pharmacological properties remains an important research focus. Hydroxysafflower yellow A (HSYA), the major bioactive component of safflower (Carthamus tinctorius L.), has demonstrated protective effects in multiple experimental models of CIS. Accumulating preclinical evidence indicates that HSYA mitigates ischemic brain injury through multiple pathways, including maintaining mitochondrial homeostasis, suppressing excitotoxicity and calcium overload, attenuating oxidative stress, inhibiting inflammatory responses, and promoting angiogenesis. However, current mechanistic evidence is predominantly derived from cellular and animal studies. Limited clinical investigations have explored the effects of HSYA-containing preparations or HSYA injection in ischemic stroke; however, current evidence remains insufficient to establish definitive clinical efficacy. The clinical efficacy, optimal dosing strategies, and long-term benefits of HSYA remain to be fully established. In addition, limited brain distribution and unfavorable pharmacokinetic properties represent important challenges for its further clinical translation. This review summarizes the current understanding of the pharmacological effects of HSYA during different phases of CIS. Furthermore, from the perspective of the stroke-heart syndrome, the potential therapeutic value of HSYA in brain-heart comorbidity is discussed. Collectively, this review provides a new perspective on the therapeutic potential and translational challenges of HSYA in CIS management.
Cancer cells undergo profound metabolic reprogramming to sustain uncontrolled proliferation within a nutrient-limited and often hypoxic tumor microenvironment (TME). Metabolic rewiring is an active driver of oncogenesis, immune evasion, epigenetic remodeling, and therapy resistance. Over the past century, our understanding of tumor metabolism has grown from Warburg's seminal description of aerobic glycolysis to a comprehensive adaptive network. Cancer cells coordinate glucose catabolism, mitochondrial oxidative metabolism, fatty acid synthesis and oxidation, amino acid catabolism, nucleotide biosynthesis, and one‑carbon metabolism into an integrated metabolic framework. These pathways form a deeply interconnected web in which metabolic intermediates serve as biosynthetic building blocks, bioenergetic substrates, redox buffers, signaling molecules, and epigenetic cofactors. Within the TME, metabolic competition between tumor cells and immune cells, together with the accumulation of immunosuppressive metabolites such as lactate, kynurenine, and adenosine, creates a profoundly immune-hostile landscape. Recent work has further revealed that key post-translational modifications, directly driven by metabolic flux, reshape the chromatin and proteome of both cancer cells and tumor-infiltrating immune cells, linking metabolism to gene regulation in previously unanticipated ways. Therapeutically, the FDA approval of IDH1/IDH2 inhibitors for acute myeloid leukemia demonstrated that metabolic enzymes are tractable oncology drug targets. Yet the broader effort to translate metabolic insights into robust clinical benefit has encountered formidable obstacles, including metabolic plasticity, intratumoral heterogeneity, overlap with normal tissue function, and inadequate biomarkers. This review traces the evolution of our understanding of cancer metabolism from its origins to therapeutic targeting. It further examines how anabolic and catabolic pathways, energy production, redox balance, and metabolic crosstalk across intracellular, intercellular, and systemic domains shape tumor biology and therapeutic response. It also critically analyzes approved and investigational metabolic therapies and charts a course for the emerging era of precision metabolic oncology.
The renin-angiotensin system (RAS) serves as a key regulator of body fluid balance and cardiovascular homeostasis, whose dysregulation is involved in the pathogenesis of various central nervous system (CNS) diseases. Beyond their canonical functions such as vascular regulation, the constituents of the RAS, particularly angiotensin (Ang) II, exert inflammatory and oxidative injury on neurons in the brain. Meanwhile, the non-classical pathway angiotensin-converting enzyme (ACE)2/Ang-(1-7) axis shows beneficial effects against CNS diseases. Activation of cerebral ACE2/Ang-(1-7) exerts regulatory effects on neurons, endothelial cells, glial cells, and other kinds, thereby comprehensively optimizing the blood-brain barrier (BBB), neurovascular unit, and cerebral microenvironment, and ultimately modulating memory, cognition, and emotion. This review, through comprehensive literature retrieval from PubMed and Web of Science, focuses on elucidating the critical regulatory role of the ACE2/Ang-(1-7) axis in CNS diseases and provides an in-depth exploration of its associated physiological and pathological mechanisms. Future research directions will primarily concentrate on novel drug development strategies targeting the ACE2/Ang-(1-7) axis, aiming to optimize drug development potential from multiple perspectives-including BBB penetration, targeted delivery to specific lesion sites, and regulation of pathological microenvironments and targets-to achieve early intervention, precision medicine, and efficient treatment for long-term CNS diseases.
Glycine transporter type 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrations, thereby maintaining the balance between excitatory and inhibitory neurotransmission in the central nervous system. GlyT1 is expressed predominantly in astrocytes, as well as in neurons, throughout most regions of the mammalian brain, and dysregulation of glycinergic transmission has been implicated in the pathophysiology of several neurological and neuropsychiatric disorders, including schizophrenia, autism spectrum disorder, Parkinson's disease, chronic pain, and epilepsy. Preclinical studies indicate that selective inhibition of GlyT1 can elevate seizure thresholds, modulate hippocampal network activity, and influence epigenetic mechanisms involved in epileptogenesis. In this review, we provide a comprehensive and critical overview of current evidence on GlyT1 as a potential molecular target for antiseizure therapy, highlighting research gaps and future directions. Despite these promising findings, the therapeutic potential of GlyT1 inhibitors remains largely unexplored in chronic and drug-resistant epilepsy models. Moreover, excessive extracellular glycine may overactivate NMDA receptors, posing a risk of adverse effects, including increased seizure susceptibility. Altogether, the preclinical data support the notion that balanced inhibition of GlyT1 may represent a novel mechanistic strategy for the treatment of epilepsy. However, further studies are required to establish its clinical efficacy, optimal dosing, safety profile, and overall therapeutic potential.
Clusterin (CLU) is a multifunctional secreted glycoprotein that is widely expressed in human tissues and body fluids. It plays critical roles in maintaining tissue homeostasis, regulating inflammation, modulating immune responses, and promoting cellular survival in both the brain and the eye. The CLU gene undergoes alternative splicing, yielding protein isoforms with distinct, and sometimes opposing, functions within a single disease condition. While secreted CLU (sCLU) is generally associated with cytoprotection, regulation of complement activation, protein chaperoning, and resolution of inflammation, the nuclear CLU (nCLU) isoform have been implicated in cell stress responses, apoptosis, and disease progression. Understanding these isoform-specific functions is essential for interpreting the diverse and sometimes contradictory roles of CLU across disease states. In this review, we discuss endogenous CLU expression, alternative splicing, and the resulting functions of its different isoforms. In addition to its inherent physiological role, we review recent research on exogenous CLU administration in the eye and brain. We identify knowledge gaps that need to be addressed before CLU is developed as a therapeutic agent. To help with the identification of future drug targets, we also summarize common CLU mechanisms in the brain and eye. By combining and contrasting knowledge from these two interconnected organs, we identify convergent CLU-regulated pathways and therapeutic opportunities, providing a comprehensive guide to future mechanistic studies, biomarker development, and CLU-based drug discovery. Therefore, the summaries in this review make it a highly relevant reference for CLU translational research and drug discovery across multiple brain and eye disorders.
Influenza virus infection remains a leading cause of acute respiratory illness worldwide, with increasing resistance to conventional antiviral therapies highlighting the need for novel therapeutic strategies. This review introduces the concept of metabolizeaccretion, a self-reinforcing pathological cascade driven by metabolic reprogramming and characterized by three progressive stages: trigger, amplification, and persistence. During influenza infection, viral-induced alterations in glucose, lipid, amino acid, and purine metabolism lead to the aberrant accumulation of metabolic intermediates, which are associated with disrupted cellular energy homeostasis, altered inflammatory and immune responses, and potential epigenetic modifications that may stabilize pathological phenotypes. These processes collectively effect viral replication, immune evasion, and progression to severe respiratory damage. We further discuss potential therapeutic interventions targeting key metabolic enzymes, accumulated metabolites, gene expression regulation, and specific receptors to disrupt metabolizeaccretion. Finally, we emphasize the importance of multi-target approaches and precision medicine strategies to address metabolic heterogeneity in lung microenvironments, offering new insights for the treatment and management of influenza and related respiratory diseases.
Ceramides (Cer) are lipid signaling molecules regulating cell proliferation, differentiation, senescence and apoptosis, whose metabolic disturbance disrupts organismal homeostasis. Accumulating evidence links ceramide imbalance to psychiatric and neurodegenerative diseases, yet few systematic reviews summarize subtype-specific ceramide functions. This review outlines ceramide anabolic and catabolic pathways, compares functional distinctions among ceramides with distinct acyl chain lengths, describes substrate preferences of ceramide metabolic enzymes, and introduces ceramide detection techniques. On this basis, we discuss regulatory roles and underlying molecular mechanisms of ceramides in schizophrenia, Alzheimer's disease, epilepsy, depression, bipolar disorder and anxiety disorders, identify disease-specific effects of distinct ceramide subtypes, and provide theoretical evidence for lipid-targeted pharmacological research on psychiatric disorders.
Different pharmacological and non-pharmacological interventions have been suggested for the management of blood glucose, among which are sodium-glucose cotransporter-2 (SGLT-2) inhibitors and exercise. SGLT-2 inhibitors (-gliflozins) are a class of drugs that reduceglucose reabsorption from the proximal renal tubule, thereby decreasing its levels in the blood, while increasing its excretion in the urine. Several studies have demonstrated cardio-, neuro-, and renoprotective benefits of these drugs, including reduced cardiovascular deaths, hospitalizations due to heart failure, rate of progression of kidney disease, cognitive deficits, reactive oxygen species, and progression of amyloid beta (Aβ) formation. Several additional mechanisms of action have been proposed for the observed benefits of SGLT-2 inhibitors. Irisin is a myokine released by skeletal muscles in response to exercise that results in browning of adipose tissue, that has been shown to have similar benefits to SGLT-2 inhibitors. Recent studies have shown that SGLT-2 inhibitors upregulate fibronectin type III domain-containing protein 5 (FNDC5) expression, from which irisin is derived, presumably by activating upstream regulators, such as adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), thereby mimicking exercise-induced pathways, contributing to their protective benefits across various organ systems. We hypothesize that activation of the PGC-1α - FNDC5/irisin axis represents a previously unrecognized downstream mediator of the pleiotropic cardiorenal and neuroprotective effects of SGLT-2 inhibitors. While current evidence is largely preclinical and associative, this framework generates a testable mechanistic model in which circulating irisin could serve both as a mediator and biomarker of SGLT-2 inhibitor-induced tissue protection.
T cell exhaustion (TCE), a hallmark of chronic infections and cancer, is characterized by progressive loss of effector function, sustained expression of inhibitory receptors, and stable transcriptional/epigenetic reprogramming. Within the tumor microenvironment (TME), exhausted CD8+ T cells fail to eliminate malignant cells, contributing to immune evasion and resistance to immunotherapy. Although checkpoint blockade has provided clinical benefit, outcomes remain variable, underscoring the need to better understand the temporal and mechanistic basis of exhaustion. Current modeling efforts have yielded valuable insights; however, they often focus on isolated aspects of tumor-immune interactions. Deterministic models such as ordinary, partial, and delay differential equations capture population dynamics, but omit stochastic variation and single-cell heterogeneity. Stochastic and agent-based models address randomness and spatial structure at a greater computational cost. Hybrid and multiscale approaches increasingly integrate these methods, but few explicitly capture the progressive, time-series nature of TCE as revealed by recent epigenetic and transcriptomics studies. This review analyzes various mathematical and computational frameworks including deterministic, stochastic, and hybrid approaches that have been applied to study TCE in viral and cancer contexts. We distinguish between TCE-specific models that directly represent exhaustion dynamics and TCE-relevant frameworks that model tumor-immune interactions, spatial tumor microenvironment features, and pharmacological interventions that could be adapted to optimize future TCE models. By comparing strengths and limitations across frameworks, we identify key gaps including limited integration of temporal resolution, lack of multiscale intracellular regulation, and scarce validation with longitudinal experimental data. We also highlight how TCE-relevant models can support pharmacological and translational questions, including dose optimization, pharmacokinetic /pharmacodynamic (PK/PD) integration, and mechanisms of immunotherapy failure. Future models that adopt hybrid, time-resolved, and multiscale designs linking intracellular regulatory networks, population-level signaling, and spatially heterogeneous TME features, calibrated with time-series omics data, would be invaluable in addressing these gaps. Such frameworks would provide mechanistic insights into exhaustion trajectories, supporting advances in immunotherapy design and clinical outcomes.
Multidrug-resistant (MDR) Staphylococcus aureus remains a leading cause of life-threatening infections worldwide and is designated a high-priority pathogen by the WHO. The accumulation of resistance mechanisms, such as β-lactam insensitivity, reduced vancomycin susceptibility, and multidrug efflux, has limited effective therapies and sustained high morbidity and mortality. Conventional antibiotic discovery is too slow, costly, and inefficient to keep pace with resistance. Artificial intelligence-driven drug design (AIDD) has emerged to address these limitations through high-precision virtual screening, generative de novo design, and multi-parameter property optimization. This review synthesizes the clinical burden and resistance mechanisms of MDR S. aureus, evaluates AIDD technologies spanning data resource curation, resistance prediction, generative design, and structure-based optimization, and examines the structure-activity relationships (SAR) that guide rational anti-staphylococcal design. By integrating AI methodology with antibacterial pharmacology, it illustrates how AI-driven approaches can accelerate the discovery of novel antibiotics against MDR S. aureus and other priority pathogens.
Cardiovascular-kidney-metabolic (CKM) syndrome, formally defined by the American Heart Association in 2023, affects approximately 90% of US adults, who meet criteria for stage 1 or higher. The rapid convergence of multiple drug classes on CKM pathways, SGLT2 inhibitors, finerenone, GLP-1 receptor agonists, ARNI, and interleukin-directed therapies, has created an urgent need for pharmacologically grounded frameworks that guide drug selection, interpret biomarker responses, and monitor target engagement across interconnected organ systems. This review proposes a three-dimensional biomarker-guided approach to precision pharmacotherapy in CKM syndrome. In the organ-specific dimension, we map key biomarkers to their corresponding drug targets and elucidate the molecular mechanisms underlying drug-biomarker interactions: SGLT2 inhibitors attenuate myocardial injury through metabolic substrate shifting toward ketone body utilization and, based on preclinical evidence, NHE1 inhibition; neprilysin selectivity of sacubitril/valsartan explains the differential natriuretic peptide response; and tubuloglomerular feedback mediates the renoprotective hemodynamic effects of SGLT2 inhibitors. In the pathway-specific dimension, we identify cross-system biomarkers, such as hs-CRP, IL-6, galectin-3, GDF-15, and FGF21,which reveal shared druggable targets spanning the IL-1β/NLRP3 inflammasome axis (canakinumab, colchicine), IL-6 trans-signaling (ziltivekimab), and FGF21/β-klotho metabolic signaling. In the temporal dimension, we demonstrate how serial biomarker trajectories serve as pharmacodynamic readouts that distinguish therapeutic drug effects from disease progression, including the initial eGFR dip with SGLT2 inhibitors and natriuretic peptide changes during combination therapy. Central to this framework is the concept of "pharmacological phenotyping", using multi-biomarker panels to define drug-responsive pathophysiological states that directly inform therapeutic selection, analogous to companion diagnostics in oncology. We further present a comprehensive drug-biomarker interaction matrix with pharmacological rationale and analyze the emerging drug development pipeline, including RNA-based Lp(a) therapeutics, FGF21 analogues, galectin-3 inhibitors, and in vivo CAR-T anti-fibrotic approaches. This framework provides a practical roadmap for biomarker-guided precision pharmacotherapy in CKM syndrome.
Pulmonary arterial hypertension (PAH) is a severe, progressive hemodynamic disorder characterized by pathological pulmonary vascular remodeling and right ventricular dysfunction, in which metabolic reprogramming is recognized as a pivotal pathogenic mechanism driving disease progression. This review synthesizes the metabolic pathways, key regulatory targets, and therapeutic implications underlying PAH pathogenesis, focusing on the major cell types involved in its pathogenesis: dysfunctional pulmonary arterial endothelial cells (PAECs), abnormally proliferating pulmonary arterial smooth muscle cells (PASMCs), activated pulmonary artery adventitial fibroblasts (PAAFs), infiltrating immune cells, and right ventricular cardiomyocytes (RVCMs) that undergo compensatory remodeling to counteract increased pressure overload. The primary highlight is its cell-specific analytical framework, which systematically delineates shared metabolic hallmarks and distinct cell-type-specific mechanisms. Shared metabolic features across these cell populations include enhanced aerobic glycolysis, impaired mitochondrial oxidative phosphorylation, and dysregulated amino acid metabolism. Cell-specific mechanisms encompass dysfunction of PAECs, phenotypic switching of PASMCs, PAAFs-mediated adventitial fibrosis, metabolic inflexibility of RVCMs, and inflammatory polarization of immune cells. By integrating these multifaceted findings, the review provides critical insights into the metabolic underpinnings of PAH, emphasizing cell-specific metabolic regulation as a strategy for targeted therapy to reverse vascular remodeling, mitigate right ventricular dysfunction, and improve clinical outcomes.
Long-chain metabolites produced through hepatic and microbiota-associated ω-oxidation of vitamin E are increasingly recognized as bioactive regulators of lipid metabolism and inflammatory pathways. These properties suggest interesting opportunities in drug development and garcinoic acid (GA) - a δ-tocotrienol-derived natural product and a chemically accessible analogue of these metabolites - is a useful probe for investigating their molecular and pharmacological properties. GA has been identified as an agonist of pregnane X receptor, a modulator of peroxisome proliferator-activated receptor γ, and an inhibitor of enzymes involved in biosynthesis of inflammatory lipid mediators, including 5-lipoxygenase and microsomal prostaglandin E₂ synthase-1, while its effects on cyclooxygenase pathways are context-dependent. Through these activities, GA functionally links xenobiotic sensing, lipid metabolism, and inflammatory regulation across selected tissues, including the intestine, liver and brain. GA can be viewed within the broader framework of metabolite-inspired pharmacology, highlighting how plant-derived natural products that mimic endogenous or microbiota-associated metabolites may carry privileged recognition motifs for pharmacological targets. These aspects, together with the biological effects of GA identified in preclinical models, suggest therapeutic potential. However, direct applications are constrained by unfavorable pharmacokinetic properties, supporting its use as a biomimetic scaffold for the design of improved modulators inspired by vitamin E metabolite biology.
In Alzheimer's disease (AD), pathological changes start decades before symptoms appear; by the time cognitive issues are noticeable, widespread neuronal and glial dysfunction and significant neuronal loss have already occurred. Recent regulatory approvals of monoclonal antibodies targeting aggregated amyloid-β (Aβ) species, including oligomers and fibrils, represent a major advance in disease-modifying therapy. However, therapeutic efficacy is strongly dependent on intervention at the earliest pathological stages, underscoring the importance of early diagnosis and treatment. Early diagnosis requires biomarkers that accurately reflect the initiation and progression of AD pathology as well as the development of methodologies capable of capturing these pathological states in vivo. Effective early treatment necessitates strategies that suppress the formation, activation, or toxicity of molecules that trigger downstream neurodegenerative cascades, thereby interrupting disease progression at its source. In parallel, advances in targeted brain delivery technologies are essential to enable sensitive detection and effective therapeutic modulation of central nervous system targets. Neurotheranostics is an integrated conceptual framework that aims to achieve early diagnosis and targeted therapy either simultaneously or in a coordinated manner using shared molecular targets and biological readouts. By unifying molecular imaging, biomarker analysis, and disease-modifying intervention, neurotheranostics aims to overcome the limitations of conventional diagnostic and therapeutic paradigms in neurodegenerative disorders, including AD. In this review, we summarize recent advances in neurotheranostic approaches for AD and highlight emerging molecular probes, low-molecular-weight compounds, and delivery technologies, including contributions from our studies.
Standard modifiable cardiovascular risk factors (SMuRFs) and non-SMuRFs are commonly used for risk stratification and therapeutic guidance after ST-elevation myocardial infarction (STEMI) in the general population. Their prognostic relevance with a potential implication for pharmacological and therapeutic management in individuals with established diabetes remains uncertain. This systematic review with meta-analysis aimed to identify prognostic factors associated with mortality in individuals with diabetes and STEMI qualifying for potential therapeutic targets. Studies evaluating prognostic factors for mortality in individuals with diabetes after STEMI were included up to May 3, 2025. Data extraction was performed independently by two reviewers. Certainty of evidence (CoE) was evaluated (GRADE). Thirty-seven studies were included, of which 25 had a high risk of bias. Mortality after STEMI in individuals with diabetes was consistently associated with non-SMuRFs (age, female sex, chronic kidney disease), acute cardiac dysfunction (Killip class III-IV, heart failure, cardiogenic shock), and atherosclerosis extent (anterior infarction, prior myocardial infarction, peripheral vascular disease). Diabetes-specific risk factors, including glycemic control parameters and insulin treatment, were also associated with increased risk of mortality (low to very low CoE). Once diabetes is established, no increased risk of mortality was observed for traditional SMuRFs, such as hypertension, smoking status, dyslipidemia, and obesity. These findings highlight the need for therapeutic strategies beyond conventional risk factor modification, with emphasis on acute hemodynamic management, tailored pharmacotherapy, and optimized glycemic control in this high-risk population. REGISTRATION PROSPERo: CRD42022378193.
Beyond their canonical role in bioenergetics, mitochondria are now recognized as critical signaling platforms that orchestrate innate immune responses. Central to this function is mitochondrial dynamics-the controlled equilibrium between fission and fusion-which serves as a critical structural and thermodynamic checkpoint for cellular fate and immunological status. A substantial body of evidence indicates that pathological mitochondrial fission, frequently driven by Dynamin-related protein 1 (Drp1), is a hallmark of numerous inflammatory conditions. Mechanistically, fragmented mitochondria release damage-associated molecular patterns (DAMPs) and induce acute ATP suppression, metabolically "licensing" NLRP3 activation by collapsing the ATP hydrolysis potential (ΔGATP). Recent breakthroughs have redefined this axis, distinguishing between physical damage and metabolic triggers, such as pyrimidine imbalance via the YME1L-SLC25A33 axis. Furthermore, the immunogenicity of DAMPs is strictly context-dependent; oxidized or "fragile" mtDNA containing ribonucleotides act as hyper-immunogenic ligands for cytosolic sensors like cGAS-STING. Emerging evidence further highlights that endosomal-mitochondrial crosstalk, intercellular mitochondrial transfer, and lipid-driven metabolic rewiring profoundly govern macrophage polarization and tissue homeostasis. Conversely, promoting mitochondrial fusion and robust quality control preserves organellar integrity and attenuates inflammatory cascades. This review critically synthesizes current literature, deconstructing the molecular linkages between organelle structure and metabolic signaling. By exploring the consequences in sepsis, neuroinflammation, osteoarthritis, and cancer, this treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.
Protein acetylation (commonly termed lysine acetylation) is a dynamic and ubiquitous post-translational modification (PTM). It is governed by two opposing enzyme families: lysine acetyltransferases (KATs) mediate acetyl group addition to target lysine residues, while lysine deacetylases (KDACs) facilitate their removal. Emerging evidence highlights the crucial regulatory role of protein acetylation in transcriptional regulation, DNA damage response modulation, cytoskeletal remodeling, autophagic flux regulation, and others processes that are involved in fibrotic pathogenesis. Fibrosis is characterized by excessive extracellular matrix (ECM) deposition and represents a pathological wound-healing response to chronic tissue injury. This response leads to organ dysfunction in multiple systems, including the heart, liver, lungs, and kidneys. Based on above findings, this review systematically summarizes the biochemical characteristics of protein acetylation and its role in tissue fibrosis, discusses the interplay between acetylation and other PTMs; finally proposes therapeutic opportunities. In conclusion, this review aim to comprehensively describe protein acetylation's role in tissue fibrosis pathogenesis across organs, highlighting recent advances in targets, profiling techniques, and therapies, while identifying knowledge gaps and future directions.
