Fluvoxamine Maleate (FM) is a selective serotonin reuptake inhibitor (SSRI)that has attracted increased attention owing to its strong agonistic activity at the Sigma 1 Receptor (σ1R). This review consolidates current understanding of its processes highlighting σ1R-mediated chaperone activity in the ER which alleviates protein misfolding, ER stress and neuroinflammation in mental and neurological illnesses.Fluvoxamine demonstrates one of the highest affinities for σ1R among SSRIs exceeding that of sertraline and fluoxetine via dissociating σ1R from BiP chaperones to improve protein refolding and cellular resilience. Preclinical experiments illustrate its inhibition of unfolded protein response indicators, reinstatement of glutamatergic transmission and stimulation of parvalbumin interneurons resulting in antipsychotic-like effects in schizophrenia and neuroprotection against ketamine-induced impairments.In addition to serotonin reuptake inhibition fluvoxamine influences inflammation, apoptosis and extracellular matrix dynamics. Supplementary activities include advantages against tardive dyskinesia and cognitive improvement in depression by mitigating stress induced neuronal atrophy. Repurposing initiatives underscore fluvoxamine's potential beyond OCD and depression. σ1R agonism is fundamental to its effectiveness in disorders caused by ER stress such as schizophrenia, tardive dyskinesia and may be neuropsychiatric sequelae associated with protracted COVID. Clinical translation encounters obstacles in dose optimization and σ1R selectivity; yet, current studies highlight its multimodal efficacy for neurodegeneration, fibrosis, and psychopharmacology.
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are common critical illnesses, with few effective therapies targeting their core pathological mechanisms. Current research confirms that mitochondrial dysfunction and excessive formation of neutrophil extracellular traps (NETs) play important roles in the occurrence and progression of ALI. Mitochondrial metabolic abnormalities can increase reactive oxygen species (ROS) production and promote mitochondrial deoxyribonucleic acid (mtDNA) liberation, both of which may participate in the initiation and amplification of NETs. Meanwhile, neutrophil extracellular trap (NET) components, such as neutrophil elastase (NE) and myeloperoxidase (MPO), may further disturb mitochondrial homeostasis in pulmonary structural cells, thereby aggravating inflammatory responses and tissue injury. Increasing evidence suggests bidirectional interactions between mitochondrial abnormalities and excessive NET formation, although the NET-to-mitochondrial arm remains less directly established in ALI. Based on this understanding, recent studies have begun to focus on therapeutic strategies that simultaneously regulate mitochondrial metabolic status and NET formation. For example, improving mitochondrial function or regulating metabolic pathways to reduce excessive NET formation, and directly clearing or inhibiting NETs through deoxyribonuclease (DNase) or peptidylarginine deiminase 4 (PAD4) inhibitors, have shown certain potential in animal models. However, related clinical evidence remains limited, and treatment timing and safety issues require further clarification. This review summarizes recent progress in mitochondrial metabolic reprogramming and dynamic changes in NETs in ALI, with emphasis on the potential connections between these two processes and their therapeutic significance, providing a reference for future mechanistic research and clinical translation.
Arginine vasopressin (AVP), a nonapeptide produced mainly in hypothalamic neurons, is known for regulating osmotic balance and blood vessel tone. Recent evidence shows it also plays key roles in the immunoneuroendocrine axis, reproduction, and cellular stress. This review explores its role as an immune regulator involving hypothalamic signals, organ responses, and inflammation. We cover AVP's structure, receptor types (V1a, V1b, V2), pharmacological analogs, and their interactions with cytokines and immune cells. Experimental and translational data indicate that AVP exerts context-dependent effects on inflammation, either amplifying or constraining immune activation, depending on receptor engagement, the signaling milieu, and the tissue microenvironment. V1a receptor-mediated vasoconstriction, endothelial dysfunction, and pro-inflammatory signaling (including NF-κB and inflammasome activation) can contribute to microcirculatory impairment and organ injury in pathological states, whereas V2 receptor activation may mediate anti-inflammatory and cytoprotective effects in selected settings. These actions are not fixed to individual receptor subtypes but are shaped by dose, disease stage, and host neuroendocrine status. Receptor-specific modulation influences cytokine profiles, leukocyte recruitment, and hypothalamic-pituitary-adrenal feedback, and has been examined in sepsis, ischemia-reperfusion injury, and autoimmune or neuroinflammatory models. Collectively, current evidence supports the AVP system as a mechanistically relevant but still largely preclinical target in inflammation-driven diseases. Potential therapeutic applications of selective AVP agonists and antagonists should therefore be considered hypothesis-generating. These applications will require rigorous validation in well-designed experimental and clinical studies before any firm recommendations can be made.
Mitochondrial dysfunction has emerged as a convergent pathogenic mechanism across inflammatory and degenerative disorders, functioning not as a passive consequence but as an active amplifier of tissue injury, immune dysregulation, and impaired repair. Consistently observed mitochondrial abnormalities include excessive reactive oxygen species production, impaired oxidative phosphorylation, defective mitophagy, altered fission-fusion dynamics, and release of mitochondrial danger-associated molecular patterns, particularly cell-free mitochondrial DNA (cf-mtDNA), which serves both as a proinflammatory mediator and a potential circulating biomarker of disease activity. These alterations create self-reinforcing networks in which mitochondrial stress promotes innate immune activation, sustains inflammatory signaling, and accelerates structural or functional decline in vulnerable tissues. Mitochondria-targeted pharmacology has expanded rapidly, encompassing organelle-directed antioxidants, modulators of mitochondrial quality control, biogenesis or metabolic enhancers, nano-enabled delivery platforms, and emerging mitochondrial replacement strategies. Despite strong mechanistic appeal and encouraging preclinical data, clinical translation remains limited by the absence of validated pharmacodynamic biomarkers, an incomplete understanding of disease endotypes, inconsistent tissue target engagement, delivery barriers to mitochondria-rich compartments, and poor predictive value of animal models for human disease biology. The cf-mtDNA and related mitochondrial signatures are increasingly attracting attention for patient stratification, phenotyping, and therapeutic monitoring, although assay standardization remains unresolved. This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression. It also examines biomarker development and the major barriers to translation. Emerging approaches such as nanotechnology and mitochondrial replacement are discussed as supplementary strategies, not as the main focus of the review.
Edaravone-Dexborneol (EDB) is a rationally engineered neuroprotective formulation that integrates the free-radical scavenger edaravone with the monoterpenoid (+)-borneol in a multimodal 4:1 M ratio. This combination was developed to overcome the translational limitations of single-target neuroprotectants by combining potent antioxidative activity with enhanced blood-brain barrier permeability, anti-inflammatory signaling, and improved pharmacokinetic behavior. This review provides a mechanistic synthesis of the multimodal pharmacology of EDB, emphasizing its associated modulation of oxidative stress, neuroinflammation, and regulated cell death pathways-including apoptosis, pyroptosis, and, in particular, ferroptosis. A structured search of preclinical and clinical literature was conducted, and study quality was appraised using established methodological frameworks to ensure a rigorous and comprehensive synthesis. Across clinical investigations, EDB consistently demonstrates superior neurological recovery and functional outcomes compared with edaravone monotherapy. Mechanistically, EDB treatment is accompanied by activation of the Nrf2/HO-1/SLC7A11 signaling cascade, concurrent with upregulation of GPX4 and reduction of iron-dependent lipid peroxidation, pointing toward a key role in mitigating ferroptotic cell death. In parallel, EDB is associated with attenuated neuroinflammatory signaling via downregulation of the TLR4/MyD88/NF-κB cascade and suppression of NLRP3 inflammasome activation. These actions are correlated with microglial polarization toward an M2 reparative phenotype, stabilization of the neurovascular unit, and reduced blood-brain barrier disruption. Collectively, the clinical and mechanistic evidence highlights EDB as a promising combination therapy that targets the intersection of oxidative stress, inflammation, and regulated cell death, providing a compelling rationale for its therapeutic potential for acute and chronic central nervous system disorders.
Venoms are complex natural secretions that contain bioactive molecules with diverse pharmacological effects. Melittin, a 26-amino-acid amphipathic peptide derived from the venom of the honeybee Apis mellifera, has been widely reported to exert cytotoxic effects in cancer models. Although melittin is best known for its membrane-disruptive and haemolytic properties, increasing evidence suggests that it also modulates intracellular signalling pathways involved in cancer progression.This review synthesised evidence on the mechanistic effects of melittin in cancer-related pathways. Articles were retrieved from PubMed, Ovid MEDLINE, and Scopus using the search terms “melittin,” “mechanism,” and “cancer.” A total of 454 records were identified. After duplicate removal and staged screening, 64 studies were included in the final synthesis. Mechanistic findings were organised according to cancer hallmark-related processes, including hypoxia-associated signalling, proliferative and survival signalling, apoptosis, cell-cycle progression, Wnt/β-catenin signalling, epithelial-mesenchymal transition, membrane disruption, and calmodulin-related mechanisms.The most consistently supported effects of melittin involved induction of apoptosis, suppression of PI3K/AKT/mTOR and MAPK/ERK signalling, inhibition of HIF-1α/VEGF-associated hypoxic and angiogenic responses, and direct membrane permeabilisation. Evidence for Wnt/β-catenin modulation, cyclin-CDK-mediated cell-cycle arrest, and suppression of EMT-associated invasive phenotypes was promising but more context-dependent. Calmodulin-related mechanisms remain plausible but insufficiently validated in contemporary cancer models.Melittin demonstrates multi-targeted anticancer activity across preclinical models, but its development is constrained by haemolytic activity, off-target cytolysis, poor oral bioavailability, and uncertain tumour selectivity. Future studies should define mechanism-exposure relationships, distinguish regulated pathway modulation from secondary cytotoxic stress responses, and prioritise targeted delivery, therapeutic index assessment, and rational sequence optimisation.
BACKGROUND:Afatinib is commonly used in the treatment of non-small cell lung cancer (NSCLC). This systematic review summarizes clinical pharmacokinetics (PK) evidence focusing on the effect of disease state and drug interactions on afatinib exposure. METHODS:Google Scholar, Science Direct, PubMed, and the Cochrane library were searched for human studies reporting the clinical PK of afatinib. The search yielded 24 articles that met the predefined inclusion criteria. RESULTS:Afatinib exposure increased slightly more than dose proportionally, with higher doses producing greater AUC0-24 and Cmax values. The apparent oral clearance reported after administration of the oral solution was lower than that observed following tablet administration. The Cmax of afatinib increases by 38.5% after coadministration with ritonavir and exposure decreases 34.3% with rifampicin. The Cmax decreases 31.45% when given with pemetrexed. Both the AUC0-24 and Cmax increase in NSCLC and tumor state. The AUC0-24 of afatinib is 2.61 folds higher following multiple oral doses among patients with solid tumors. Afatinib exposure is 22.1 % higher in renal impaired patients than in healthy controls. In grade 2 diarrhea, the AUC0-24 of afatinib is 83.93% higher as than in grade 0-1 diarrhea in solid tumor patients. CONCLUSION:This systematic review provides an updated synthesis of clinical PK evidence on afatinib. Afatinib exposure is influenced by dose, repeated administration, renal impairment, diarrhea associated toxicity, and P-glycoprotein mediated drug interactions. These findings may support individualized dosing, toxicity-guided dose adjustment, and future development of PK models for afatinib.
Alzheimer's disease (AD) is increasingly recognized as a disorder involving interacting neuroimmune, glial, vascular, and synaptic processes that are not fully captured by single-pathway therapeutic models. Although anti-amyloid monoclonal antibodies slow clinical progression in selected early amyloid-positive patients, their benefit remains stage-dependent, monitoring-intensive, and incomplete with respect to downstream neural dysfunction. Clinically, vulnerable older adults may show abrupt cognitive decline after pneumonia-related hospitalization or other severe infections. This observation raises a pharmacological question: whether infection-triggered peripheral immune events activate modifiable risk processes before they become sustained neuroimmune and synaptic dysfunction. NETosis is one candidate mechanism linking peripheral inflammatory stress to endothelial injury, blood-brain barrier vulnerability, myeloid priming, and microglial dysregulation. Acute infection may represent a high-intensity peripheral NETosis-related trigger, whereas periodontitis provides a chronic, low-grade, neutrophil-rich, microbially driven, clinically measurable, and modifiable peripheral inflammatory model. We propose a node-based pharmacological framework organized around NETosis-associated immune amplification, microglial state dysregulation, and synaptic vulnerability. Selected phytochemicals are examined as node-aligned pharmacological probes rather than validated AD therapeutics: baicalin and hesperidin for NETosis-associated immune amplification, berberine for microglial state modulation, and catalpol as a synapse-proximal candidate.
Ischemic stroke persists as a preeminent global health burden, ranking among the foremost causes of both mortality and long-term disability worldwide. This significant disease burden underscores its critical status within international public health priorities. To comprehensively address this challenge, this review adopts an epidemiological lens, systematically examining the underlying pathogenesis of ischemic stroke, evaluating contemporary clinical intervention strategies spanning prevention to acute care and rehabilitation, and critically appraising recent advances in therapeutic pharmacology. Furthermore, the review explores promising future therapeutic directions, including the ongoing quest for novel pharmacological agents and the translational potential of regenerative medicine. Collectively, this review aims to provide insights to inform evidence-based clinical decision-making while simultaneously stimulating innovative research pathways in novel pharmacotherapy development and its effective translation into clinical practice.
Ovarian aging manifests as progressive depletion of the primordial follicle reserve and declining oocyte quality, culminating in menopause and associated systemic comorbidities. Cellular senescence emerges as a central driver of this process, exerting effects through cell-cycle arrest pathways and a proinflammatory senescence-associated secretory phenotype (SASP) that disrupts the follicular niche and stromal architecture. However, current senolytic and senomorphic interventions for ovarian aging remain largely at the mechanistic and preclinical stages, and their translational potential in humans is still uncertain. This review synthesizes the molecular hallmarks of ovarian senescence-encompassing genomic instability, mitochondrial dysfunction, dysregulated nutrient sensing (PI3K/AKT/mTOR), proteostatic failure, epigenetic drift, and inflammasome activation-into a unified framework for therapeutic intervention. We critically evaluate the preclinical efficacy of senolytics (eg, dasatinib + quercetin, navitoclax, fisetin), and senomorphics (eg, rapamycin, metformin, melatonin, NLRP3 inhibitors) in preserving ovarian reserve, mitigating SASP-driven inflammation and fibrosis, and extending reproductive lifespan. Emphasis is placed on multimodal biomarkers (AMH, AFC, SASP analytes, follicular fluid signatures, exosomal RNAs) essential for clinical translation, alongside ovary-directed delivery systems to enhance specificity and safety. By bridging ovarian geroscience with emerging senotherapeutics, this review charts a roadmap for advancing these strategies from bench to bedside, offering potential to combat ovarian aging and safeguard women's reproductive and systemic health.
Chrono-immunotherapy has emerged as a compelling precision-oncology strategy based on the premise that immune checkpoint blockade is modulated by circadian biology. The immune system is organized across daily oscillations in leukocyte trafficking, cytokine production, antigen presentation, endocrine signaling, and tissue accessibility, while the tumor microenvironment itself exhibits rhythmic changes in vascular permeability, suppressive myeloid activity, and stromal reprogramming. Together, these temporal fluctuations create biologically distinct windows during which immunotherapy may be more or less effective. Retrospective clinical studies have repeatedly suggested that earlier time-of-day administration of immune checkpoint inhibitors is associated with superior survival outcomes across several malignancies, although confounding by clinic workflow and patient selection has limited causal inference. More importantly, prospective randomized evidence in non-small cell lung cancer has now demonstrated longer progression-free survival with early-day immunochemotherapy delivery, strengthening the rationale for time-directed treatment scheduling. This review synthesizes the molecular, cellular, and clinical foundations of chrono-immunotherapy, discusses biomarker strategies for chronotype assessment, and proposes a translational framework for incorporating internal biological time into routine oncology practice. We also highlight implementation barriers, methodological limitations, and future research directions required to establish chrono-immunotherapy as a clinically actionable component of precision cancer care.
Methotrexate (MTX) remains a cornerstone therapy across oncology, rheumatology, dermatology, and reproductive medicine. Despite its long clinical history, MTX exhibits mechanistic complexity that extends far beyond classical antifolate activity, encompassing immunomodulation, metabolic reprogramming, and redox regulation. These diverse actions underpin both its therapeutic efficacy and its potential for toxicity. This review synthesizes contemporary insights into MTX pharmacology, systems toxicology, pharmacokinetics, clinical applications, and precision rescue strategies, integrating multi-omic evidence and real-world data to provide a modern, mechanistically informed framework for MTX therapy. MTX exerts dose-dependent effects on nucleotide synthesis, adenosine signaling, cytokine networks, mitochondrial function, and oxidative stress pathways. Toxicity arises from interconnected disturbances in metabolic, inflammatory, and transporter systems, with organ-specific manifestations in the liver, kidney, lung, and bone marrow. High-dose MTX requires meticulous pharmacokinetic monitoring and individualized rescue strategies, including leucovorin and glucarpidase. Real-world pharmacovigilance data highlight the influence of age, sex, comorbidities, and drug-drug interactions on MTX safety. Advances in pharmacogenomics, systems biology, and computational modeling are reshaping MTX dosing, toxicity prediction, and therapeutic optimization. MTX exemplifies how a legacy drug can be continually redefined through modern science. Integrating pharmacogenomic profiling, multi-omic biomarkers, and AI-driven prediction models promises to transform MTX therapy into a fully personalized, mechanism-guided approach. These innovations will expand MTX's therapeutic window, enhance safety, and ensure its continued relevance in precision pharmacotherapy.
Alopecia areata (AA) is an immune-mediated disorder characterized by non-scarring hair loss and substantial psychosocial burden. Although recent advances have clarified key pathogenic mechanisms and expanded therapeutic options, important uncertainties persist regarding disease heterogeneity, treatment durability, and long-term safety. Central to AA pathogenesis is the collapse of hair follicle immune privilege, driven primarily by cytotoxic CD8+ NKG2D+ T-cells and sustained by interferon-γ-dependent Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. However, emerging evidence indicates immunological variability across patient subsets, including inconsistent contributions from T helper cell pathways and regulatory immune dysfunction. The clinical approval of JAK inhibitors-baricitinib, ritlecitinib, and deuruxolitinib-represents a major therapeutic milestone, validating targeted immune modulation as an effective strategy for moderate-to-severe AA. Nevertheless, relapse following treatment discontinuation, interindividual variability in response, and unresolved long-term safety considerations highlight the limitations of current approaches. In parallel, regenerative therapies, microbiome-based interventions, gene-targeted strategies, and device-assisted technologies are under investigation, yet most face substantial translational, regulatory, and scalability challenges. This review critically synthesizes current evidence on AA pathogenesis and therapy, with particular emphasis on unresolved controversies, translational barriers, and clinical implications. By integrating mechanistic insights with emerging clinical data, the article highlights priorities for future research, including biomarker development, precision medicine approaches, and strategies aimed at achieving durable disease control rather than transient immune suppression.
BACKGROUND:Depression involves multisystem alterations, including impaired neuroplasticity, inflammation, and dysregulation of immune and endocrine function. In animal studies, non-invasive regulatory interventions-such as acupuncture, electroacupuncture, repetitive transcranial magnetic stimulation (rTMS), transcvranial electrical stimulation (tES/tDCS), and transcutaneous auricular vagus nerve stimulation (taVNS)-have shown potential for alleviating depression-like behaviors. OBJECTIVE:To systematically summarize the neurological, immunological, and endocrine-related outcomes reported for non-invasive neuromodulation in animal models of depression, and to compare the potential shared downstream changes across different intervention types, as well as their similarities and differences. METHODS:A systematic search was conducted for studies using animal models related to depression. Literature screening was performed in accordance with the PRISMA reporting guidelines, and a total of 29 studies were included. These studies involved models of chronic stress, post-stroke depression, inflammation-induced depression, and depression associated with metabolic abnormalities. The interventions examined included acupuncture, rTMS, tDCS/tES, and taVNS. Behavioral outcomes and mechanistic indicators were synthesized narratively. RESULTS:Non-invasive neuromodulation acts concurrently on neural, immune, and endocrine systems: it enhances synaptic remodeling, reduces inflammatory burden, and recalibrates HPA-axis feedback, thereby interrupting vicious cycles and restoring systemic homeostasis. CONCLUSION:By simultaneously improving neuroplasticity, modulating immune-inflammatory signaling, and stabilizing endocrine function, non-invasive neuromodulation exerts antidepressant-like effects in animal models. These multisystem actions highlight its therapeutic potential, particularly for depression associated with inflammation or metabolic dysfunction. Future research should further clarify causal relationships within the neuro-immune-endocrine axis and translate these insights into optimized clinical strategies.
Neurotensin (NT) is a conserved neuropeptide acting as a critical state-dependent neuromodulator across hypothalamic, limbic, and brainstem circuits. Historically categorized by discrete behavioral effects, recent spatial transcriptomic and functional breakthroughs reveal a unifying computational logic: NT signaling modulates how neural circuits integrate and prioritize competing motivational and homeostatic signals. Crucially, NT-dependent effects emerge predominantly under physiological challenge, uncertainty, or conflicting demands, biasing the probability of behavioral outputs through conditional gain-control. This framework reconciles divergent findings and highlights NT receptors (NTSR1/NTSR2) as highly tractable pharmacological targets. The development of subtype-selective and biased agonists offers novel therapeutic avenues for modulating adaptive behavior in psychiatric, metabolic, and pain-related disorders.
Neuroinflammation and neurodegeneration are tightly interconnected processes that drive the progression of multiple central nervous system (CNS) disorders. Riluzole, a benzothiazole derivative approved for amyotrophic lateral sclerosis (ALS), has been widely investigated for its broader neuroprotective potential. Its actions include modulation of glutamatergic transmission through presynaptic inhibition and upregulation of excitatory amino acid transporters. Additionally, riluzole inhibits voltage-gated sodium channels, thereby reducing neuronal hyperexcitability and excitotoxicity. Its anti-inflammatory properties are mediated through the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and the attenuation of microglial activation, while its antioxidant effects involve the activation of the nuclear factor erythroid 2-related factor 2/heme Oxygenase-1 (Nrf2/HO-1) pathway and the preservation of mitochondrial function. These mechanisms have been supported by preclinical evidence across models of ALS, Alzheimer’s disease (AD), Huntington’s disease (HD), and spinal cord injury (SCI), with emerging clinical data supporting its broader therapeutic relevance. Although clinical findings remain limited and disease-specific, the mechanistic breadth of riluzole continues to motivate interest in its potential utility across neuroinflammatory and neurodegenerative conditions. This review synthesizes recent advances in riluzole pharmacology and outlines key considerations for future mechanistic and translational research.
Obesity, metabolic syndrome, and neurodegenerative diseases are rising together, posing a public health issue. Alzheimer's disease, often referred to as "type-3 diabetes," shows how metabolic dysfunction can drive cognitive decline through disrupting brain insulin signaling, glucose metabolism, and causing inflammation. The endocannabinoid system, especially the CB1 receptor, plays a key role. While CB1R physiologically regulates energy homeostasis, chronic overnutrition leads to its pathological overactivation. Although CB1R antagonists showed strong efficacy in animal and early clinical studies, their development was halted due to neuropsychiatric side effects, underscoring an incomplete understanding of CB1R signaling across tissues and subcellular compartments. Incretin hormones, including GLP-1 and GIP, have emerged as key mediators linking metabolic control and brain health, exerting neuroprotective effects beyond glycemic regulation. Both the CB1R and incretin signaling converge on cyclic AMP pathways, suggesting that combined therapeutic strategies could improve metabolic and cognitive outcomes.Finding CB1R in mitochondria has changed our understanding, showing that cannabinoids can directly affect how cells produce energy by slowing complex I activity and interfering with how astrocytes and neurons share energy. This suggests that neuro-metabolic diseases are mainly problems with cell structures, not just with receptors.This review brings together what is known about the CB1R paradox - the observation that this receptor, essential for normal energy homeostasis, becomes a pathological driver in conditions of chronic metabolic excess. We explore how incretins protect the brain, the critical role of mitochondrial CB1R, and how cell-type-specific CB1R signaling across neural and peripheral tissues drives both metabolic and cognitive pathology.
Trained immunity is defined as the epigenetic and metabolic reprogramming of innate immune cells, conferring enhanced or diminished responsiveness to secondary challenges following initial stimulation. Immune tolerance represents the state of immunological unresponsiveness to self-antigens or innocuous foreign antigens. Systems pharmacology approaches have emerged as essential tools for understanding and modulating these complex immunological processes. In this mini-review, we evaluate quantitative systems pharmacology (QSP) approaches which are predominantly based on ordinary differential equation (ODE) frameworks and artificial intelligence (AI)/machine learning (ML) applications in the context of trained immunity and immune tolerance. QSP models enable in silico clinical trials, thereby accelerating drug development and supporting cost-effective therapeutic decision-making. Recent advances have identified histone lactylation, particularly H3K18la, as a central epigenetic mark linking metabolic rewiring to long-term innate immune memory, revealing novel pharmacological targets including LDHA, EP300, and ACAT2. ML algorithms integrated with explainable AI frameworks have facilitated biomarker discovery and therapeutic target identification. Digital twin technology holds considerable promise for developing personalized immunomodulatory strategies. This review highlights the translational potential of systems pharmacology tools in pharmacological targeting of trained immunity and tolerance, emphasizing the convergence of computational modeling with precision medicine approaches.
