Interindividual variability in drug efficacy and toxicity remains a major challenge in clinical pharmacotherapy. Although pharmacogenomics has substantially advanced personalized medicine, host genetic variation alone cannot fully explain differences in drug disposition, response, and adverse effects. Increasing evidence identifies the human gut microbiotaas an additional, functionally relevant metabolic layer that complements host drug-metabolizing enzymes, giving rise to the field of pharmacomicrobiomics. This discipline examines bidirectional interactions between drugs and microbial communities that influence absorption, metabolism, enterohepatic circulation, and pharmacodynamic outcomes. The gut microbiota can directly biotransform or sequester drugs through diverse enzymatic reactions, including deconjugation, reduction, and decarboxylation, thereby modifying systemic drug exposure and toxicity. In parallel, microbially derived metabolites and bile acid-mediated signaling pathways regulate host drug-metabolizing enzymes and transporters, including cytochrome P450 enzymes and ATP-binding cassette transporters. Conversely, many commonly used medications-such as antibiotics, chemotherapeutic agents, targeted therapies, immunotherapies, psychotropic drugs, and proton pump inhibitors-can substantially reshape microbial composition and function, resulting in dysbiosis that feeds back onto drug metabolism and therapeutic outcomes. This review summarizes the mechanistic basis and clinical relevance of microbiota-drug interactions across key therapeutic areas, including oncology (chemotherapy and immunotherapy), neuropsychiatric disorders, and metabolic diseases. Well-established examples, including microbial β-glucuronidase-mediated reactivation of irinotecan, microbiota-dependent modulation of levodopa and antidepressant pharmacokinetics, and microbiota-driven variability in immune checkpoint inhibitor efficacy, are discussed to illustrate causality. Emerging microbiome-informed strategies-such as selective inhibition of microbial enzymes, microbiota modulation, and microbial biomarker-based patient stratification-are highlighted. Finally, we examine integration of pharmacomicrobiomics with pharmacogenomics within multi-omic and systems pharmacology frameworks, emphasizing implications for predictive modeling and precision drug metabolism.
New drug modalities (NDMs) continue to redefine the pharmaceutical landscape by addressing "undruggable" targets and providing innovative therapeutics for various diseases. This third annual review summarizes 15 selected publications from 2025 that advance our understanding of NDM metabolism. We focus on four major categories: (1) PROTACs and molecular glues, with an emphasis on biotransformation and chiral stability; (2) Oligonucleotide therapeutics, including in vitro and in vivo metabolism of oligonucleotides as well as a workflow for metabolite identification; (3) Macrocyclic peptides, highlighting throughput enhancements and leader-independent cyclization; and (4) Conjugated drugs, encompassing antibody-drug conjugates (ADCs) and novel Fc-fusion proteins. This collection provides critical insights into metabolism, tissue distribution, and analytical innovations intended to accelerate the transition of these complex modalities from discovery to clinical application.
Emerging evidence suggests hepatocyte-derived extracellular vesicles (hd-EVs) may transport drug-metabolizing enzymes across the BBB. This liver-brain metabolic axis remains a conceptual model that requires in vivo validation of localized brain metabolism following EV transfer. The traditional liver-centric paradigm cannot fully explain CNS-specific drug effects, such as phenytoin induced neurotoxicity and acetaminophen-linked neuroinflammation, which occur without substantial brain drug accumulation. We propose that EVs function as systemic metabolic shuttles, transporting catalytically active xenobiotic metabolizing enzymes (XMEs), including cytochrome P450s, UDP glucuronosyltransferases, and glutathione S-transferases from hepatic tissues across the BBB to enable localized drug metabolism within the CNS. Circulating EVs can carry xenobiotic-metabolizing enzymes that retain catalytic activity, and their cargo appears to be modulated by hepatic stress and drug exposure. Some studies also suggest that EVs are capable of crossing the BBB via receptor-mediated endocytosis and being internalized by brain cells. Critical limitations remain in demonstrating direct catalytic activity of EV delivered enzymes within brain resident cells and understanding the molecular mechanisms governing enzyme cargo selection and brain specific targeting. If confirmed, EV-mediated XME transport has the potential to transform neuropharmacology by reframing the brain as a metabolically active organ supported by systemic vesicle communication. This review details the justification for this new theory as well as potential testing methods.
Introduction: Zanthoxylum rhetsa (ZR) is a medicinal plant native to Southeast Asia, widely used in traditional medicine. Despite its medicinal importance, systematic documentation of isolated bioactive constituents and their therapeutic relevance remains scarce. This systematic review aimed to compile phytochemical profile of ZR and summarize evidence on its bioactive/drug-like phytoconstituents and compound-specific biological activities, highlighting its potential as source of natural therapeutics.Methodology: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search of PubMed, Scopus, and Web of Science was conducted, and duplicates were removed using Rayyan software.Result: Compounds isolated from ZR were found to confer significant cytotoxic, antimicrobial, anti-inflammatory, antioxidant, anti-photaging, antispasmodic, and antidiarrheal effects. Mechanistic investigations revealed that several compounds exhibited selective cytotoxicity against cancer only, inhibited microbial proliferation through membrane disruption, and modulated signaling pathways associated with inflammation and oxidative stress. Additionally, absorption, distribution, metabolism, excretion (ADME) analysis highlighted nitidine, dihydrochelerythrine, and hesperidin isolated from ZR as promising drug leads with favorable pharmacokinetic and safety profiles.Conclusion: ZR constitutes a chemically diverse reservoir of bioactive metabolites, highlighting its significance as promising natural source of drug-like compounds and emphasizing the need for comprehensive mechanistic, pharmacological, and clinical investigations to evaluate therapeutic translation.
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, in which metabolic reprogramming plays a critical role in disease progression and organ failure. Metabolic reprogramming involves alterations in glucose, lipid, and protein metabolism, leading to imbalanced energy production, immune dysregulation, and tissue damage. Immune cells, under septic stress, switch to aerobic glycolysis, enhancing energy production but causing lactate accumulation and mitochondrial dysfunction, which exacerbates inflammation and organ injury. This metabolic shift emphasizes the need for personalized therapeutic strategies that address the metabolic heterogeneity between pathogens and hosts. The peroxisome proliferator-activated receptor (PPAR) pathway serves as a central regulator of both metabolic and immune responses, offering protective effects through the promotion of fatty acid oxidation and suppression of inflammation. However, the translational application of PPAR-directed therapies is constrained by limited drug specificity and significant interpatient heterogeneity. Advances in multiomics technologies provide promising opportunities for identifying metabolic biomarkers and tailoring PPAR-targeted treatments. Future research should focus on integrating metabolic pathways, developing precise diagnostic tools, and refining personalized interventions to improve sepsis management and patient prognosis. Unlike previous reviews that primarily focus on general immunometabolic alterations in sepsis, this review is the first to systematically integrate PPAR isoform-specific regulatory mechanisms, multiomics-based patient stratification, and phenotype-driven therapeutic targeting, thereby offering a novel framework for precision medicine in sepsis management. We critically evaluate the controversies on the efficacy of PPAR agonists, highlight cross talk with HIF-1α/NF-κB/Nrf2, and propose a phenotype-based stratification for sepsis therapy, a perspective that has not been explored in the literature.
Inflammatory diseases pose a major global health challenge, encompassing a wide range of chronic conditions driven by persistent inflammation. Emodin is a natural anthraquinone compound extracted from traditional Chinese medicinal herbs, exhibiting remarkable anti-inflammatory properties by regulating multiple inflammation-related signaling pathways. Despite its promising applications in the treatment of inflammatory diseases, issues such as poor water solubility, low bioavailability, rapid metabolism, and potential toxicity have limited its clinical translation. This review systematically reviews drug delivery systems (DDS) designed to overcome these limitations, with a focus on technological platforms including nanoparticles, liposomes, microspheres, nanocapsules, self-emulsifying systems, and microbubbles. Studies have shown that these platforms, through stimulus-responsive mechanisms and various targeting strategies, can significantly enhance emodin's solubility, stability, targeted delivery, and sustained-release effects, thereby improving bioavailability, reducing systemic toxicity, and strengthening anti-inflammatory efficacy. This review emphasizes the analysis of the design principles, mechanisms of action, and translational prospects of each system, while discussing challenges such as biocompatibility, stability, and scalable production, to fully exploit emodin's multi-target therapeutic potential and provide valuable references for researchers engaged in the development of anti-inflammatory DDS.
Type 2 diabetes (T2D) is closely linked to β-cell dysfunction. Preserving β-cell function has emerged as a critical therapeutic strategy for T2D. Mesenchymal stem cells (MSCs) have demonstrated remarkable potential in achieving this goal. This paper systematically reviews the multifaceted mechanisms by which MSCs protect pancreatic β-cell function in T2D. It integrates eight core mechanisms: modulating the inflammatory microenvironment, regulating the immune system, counteracting oxidative stress, enhancing autophagy levels, alleviating endoplasmic reticulum stress, safeguarding mitochondrial function, promoting β-cell regeneration and repair, and inhibiting ferroptosis. Together, these form a multi-layered, networked intervention system. This framework elucidates MSC protective effects across three functional levels: eliminating injury initiators, maintaining cellular homeostasis, and intervening in cellular fate outcomes. Additionally, this review examines pharmacological strategies to enhance MSC efficacy, including hypoglycemic agents, other drugs, and natural products, with a focus on their mechanisms of action and barriers to clinical translation. Finally, based on MSC advantages and existing research limitations, we propose future research directions, including optimizing MSC source selection and engineering MSC-derived exosomes. These recommendations aim to provide theoretical foundations and strategic references for MSC-based T2D therapies.
Kinetic isotope effects (KIEs) have been used to study mechanisms of cytochrome P450 (P450, CYP) reactions and are the basis of most applications for deuterated drugs. However, the complexity of KIEs has led to limited use and to some erroneous conclusions. Kinetic data for the 21-hydroxylation of the steroid 17α-hydroxyprogesterone by P450 21A2 (Pallan et al.) were utilized with modern kinetic analysis software (KinTek Explorer®) and simplified models. Reanalysis confirms the importance of several previous observations: (i) KIEs on the ratio kcat/Km (D(V/K), i.e. H(kcat/Km)/D(kcat/Km)) are most relevant; (ii) proper modeling of P450 reactions requires consideration of side reactions, both for substrate(s) oxidation and oxygen reduction, and (iii) a slow rate constant for a step(s) following product formation has a dramatic effect on D(V/K) due to perturbation of Km. Some applications of KIEs to the design and development of deuterated drugs are presented.
Conjoined twins present a rare but clinically challenging scenario requiring highly individualized pharmacologic strategies. Anatomical fusion, shared circulatory systems, and organ overlaps complicate drug absorption, distribution, metabolism, and excretion, including the neonatal intensive care unit setting and perioperative care. This review aims to synthesize current evidence and clinical experience regarding pharmacotherapy in CTs, focusing on drug selection, therapeutic drug monitoring and individualized dosing strategies based on anatomical and physiological variations. We performed a comprehensive structured literature review using PubMed database, covering the period 1970-2025, restricted to English-language publications. Case reports and reviews relevant to pharmacology in CTs were included (n = 4/93); surgical, radiological or anesthetic-only reports without pharmacologic content were excluded. We integrated these findings with two case reports involving pygopagus and thoracopagus conjoined twins treated in our tertiary referral care hospital. Key pharmacokinetic variables such as volume of distribution, renal clearance, and enteral absorption were examined in relation to the cross-circulation status. Additionally, an online quiz was conducted among clinicians to assess baseline knowledge. Our results observations suggest that drugs such as amikacin require TDM-based adjustments in the presence of cross-circulation in both subjects. Shared renal or gastrointestinal anatomy further necessitates titrated and monitored dosing regimens. Emergency medication strategies should consider whether complete, partial, or absent circulatory sharing is present. Questionnaire data revealed unexpectedly high knowledge levels among physicians and pharmacists, though further educational enhancements-such as virtual reality simulation and tailored protocols-are recommended. Pharmacologic management in CTs demands a multidisciplinary approach, close monitoring, and careful documentation. Case-based strategies and educational reinforcement can reduce risk and improve outcomes. Further research, including the establishment of central registries and the use of physiologically based pharmacokinetic modeling, is essential to inform individualized care in this very rare population.
Through the intake of dietary phytochemicals and herbal drugs, humans are exposed to a great number of natural products that can be either beneficial or detrimental to health outcomes. Phytochemicals from foods and medicinal plants, often referred to as secondary metabolites to emphasize their difference from metabolites produced by primary metabolism, contribute not just to occasional but long term or life-long exposure. While pharmacological actions of synthetic drugs are closely tied to changes in gene expression, the same holds true for foods and herbal drugs, but the wealth of research data is heterogeneous. This original review article attempts to clarify the exact mechanisms of gene regulation or expression by natural products through direct or indirect effects on transcription factors or epigenetic changes, with a focus on frequently occurring pathways and phytochemical classes. This review points at recent pharmaceutical drug development that arose from the investigation of natural products in food ingredients and herbal medicines and carefully evaluates negative effects on gene expression, which can lead to disease or reduced life expectancy. This article reviews seven relevant natural substance classes according to their approximate frequency in common foods and medicinal plants, and discusses general or more discrete effects on gene expression according to structure-activity relationships (SARs).
Traditional Chinese medicine(TCM) active compounds possess unique structural diversity and drug-like properties. However, elucidating their specific targets and mechanisms of action remains challenging. Traditional methods have limitations in systematically analyzing their true modes of action under physiological conditions, which constrains their application and development in new drug research and development. Activity-based protein profiling(ABPP) technology is an interdisciplinary approach integrating organic chemistry, proteomics, and bioinformatics, and has become a powerful tool in proteomics research. With technological advancements, ABPP has evolved into a relatively mature method for studying the targets of TCM. This article systematically elaborates the fundamental principles and detailed workflow of ABPP technology, summarizes the types and functions of probe groups used in ABPP, and reviews the progress of this technology in target research for TCM. It provides a systematic reference for the construction and labeling of activity-based probes and the enrichment of target proteins, aiming to facilitate in-depth research on the action targets of active ingredients in TCM, elucidate their mechanisms of action, optimize drug development processes, enhance the modernization of TCM, and accelerate the development of new drugs based on TCM.
Brain tumors remain among the most lethal cancers, in part due to the limited ability of therapeutic agents to reach malignant cells protected by the blood-brain barrier (BBB). This specialized vascular interface preserves neural homeostasis through several mechanisms and different elements. In brain malignancies, the barrier may be disrupted, remodeled, or remain largely intact depending on tumor type, leading to highly variable effects on different therapeutic approaches. These challenges have driven the development of innovative delivery strategies, including molecular engineering, nanocarriers, receptor-mediated transport systems, focused ultrasound, and direct regional administration. Understanding BBB biology and its tumor-specific alterations is essential for designing effective therapeutic approaches capable of improving outcomes in brain cancer. Recent studies showed promising results with different approaches, including pharmacological approaches, nanotechnology-based approaches, physical disruption techniques, biological and cellular approaches, and convection-enhanced delivery. This review summarizes the current understanding of the role of BBB in brain cancer, and reviews emerging strategies to overcome this barrier and enable effective brain cancer therapy. Brain tumors are among the deadliest cancers because many treatments cannot reach the tumor cells. This is largely due to the blood–brain barrier, a natural protective system that controls what substances can enter the brain to keep it healthy. In brain cancers, this barrier can behave differently: in some tumors it is damaged, in others it changes shape, and in some it stays mostly intact. Because of this, treatments that work for one brain tumor may not work for another. To overcome this problem, researchers are developing new ways to deliver drugs to the brain. These include designing drugs that can cross the barrier more easily, using nanoparticles, taking advantage of natural transport systems in blood vessels, applying focused ultrasound to temporarily open the barrier, and delivering treatments directly to the brain or tumor area. A better understanding of how the blood–brain barrier works—and how it changes in different brain tumors—is critical for creating more effective treatments. This review explains what is currently known about the blood–brain barrier in brain cancer and highlights new strategies aimed at improving drug delivery and patient outcomes.
We conducted a literature review of preclinical, animal and human pharmacology, pharmacokinetics, and pharmacogenomics related to disorders of gut-brain interaction (DGBI). This article reviews animal models of visceral pain, abnormal motility, and epithelial transport, and human models of motility and sensation and their utility in drug development for DGBI with focus on colorectal and gastric biomarkers. We highlight preclinical studies related to pharmacology, pharmacokinetics, and toxicology required for development of novel therapeutic agents, and principles of pharmacogenomics based on drug metabolism and the few examples of pharmacogenetics related to targets in treatment of IBS. Finally, we summarize the human pharmacology of medications used for treatment of DGBI based on the individual indications - specifically psychopharmacologic and nonpsychotropic agents for DGBI associated with dyspepsia, constipation, diarrhea, and visceral pain, as well as introduction of biomarkers for individualizing therapy for IBS and recommendations for future research.
ALDH1A family enzymes (ALDH1A1, ALDH1A2, and ALDH1A3) catalyze retinoic acid synthesis, and their dysregulation is linked to disease. Selective inhibitors of these enzymes have been tested in drug discovery programs and one such compound, WIN18,446, was found to irreversibly inhibit ALDH1A2. WIN18,446 is a reversible male contraceptive in humans and animals. The inhibition of spermatogenesis by WIN18,446 is thought to be due to inhibition of ALDH1A. However, the mechanism of irreversible inhibition of ALDH1A2 by WIN18,446 is not known. A crystal structure obtained after incubating ALDH1A2 with WIN18,446 revealed a WIN18,446-derived metabolite covalently adducted to the catalytic cysteine, C320. Inspection of this structure suggested that the observed adduct is unstable and may be a metabolic intermediate stabilized under crystallographic conditions. In the current work, we tested this hypothesis. We identified and characterized an aldehyde metabolite of WIN18,446, which we designated M-54. M-54 is likely the metabolite of the intermediate observed in the crystal structure. Using a range of proteomics techniques, we identified a WIN18,446-derived ALDH1A2 protein adduct of mass 292.07 Da on C319 of ALDH1A2. This adduct may result from reaction of the crystal structure metabolic intermediate. Using the identified mass, we probed human liver samples from multiple donors and found WIN18,446 specific adducts on cysteines within the ALDH1A1 and ALDH2 active site regions. The current study provides new insight into the metabolism of WIN18,446 and the mechanism of inhibition of ALDH1A2. We also demonstrate a proteomics workflow for identifying and validating drug-protein adducts of unknown mass.
With the increasing demand for feed additives that are green, safe, and free of drug residues, methylsulfonylmethane (MSM) has received extensive attention in animal production, and the research has been deepening. MSM is a sulfur-containing organic substance that is widely distributed in nature, with many biological functions, including antioxidant, anti-inflammatory, immune regulation, improvement of intestinal health, joint protection, and skin and hair nourishment, etc. It plays an important role in maintaining normal metabolism in the body and has considerable potential for application in the healthy rearing of animals. This paper reviews the biological functions and regulatory mechanisms of MSM, as well as its applications in animal production, including improving growth performance, reducing lipid peroxidation, improving meat quality, increasing disease resistance, and enhancing anti-stress ability. This is done in order to provide a reference for subsequent scientific research.
Glioblastoma (GBM) remains one of the most lethal brain malignancies because of its highly immunosuppressive tumor microenvironment and the limited penetration of therapeutics across the blood-brain barrier (BBB). Although recent studies have separately explored STING agonism, microglial reprogramming, and nanocarrier-based drug delivery, an integrated framework combining these strategies for GBM immunotherapy is still lacking. In this review, we present a new dual-function lipid-based nanovector (LNV) strategy that simultaneously activates the cGAS-STING pathway and induces tumor-associated microglia to repolarize toward the antitumor M1 phenotype. In contrast to previous reviews, which address them as individual approaches, herein we consolidate these into an integrated therapeutic paradigm and provide a rational design roadmap based on drug cargo selection, lipid isoform composition, BBB targeting, and thermo-/magnetically responsive release. We summarize how STING activation enhances type I interferon signaling, dendritic cell maturation, and cytotoxic T-cell priming, while M1-polarized microglia potentiate local inflammatory and phagocytic antitumor responses. In addition, we summarize the current nanocarrier platforms, preclinical evidence, and translational design considerations pertinent to this combinatorial approach. This review provides a conceptually integrated overview of the potential of dual-action lipid nanovectors to overcome clinically relevant immunological and delivery barriers in GBM, as well as future directions for next-generation nano-immunotherapies.
Resmetirom is an oral, liver-targeted medication that selectively activates the thyroid hormone receptor beta (THRB) and thereby targets multiple pathophysiological mechanisms of metabolic dysfunction-associated steatohepatitis (MASH). By activating hepatic THRB, resmetirom promotes fatty acid oxidation, improves mitochondrial function, inhibits de novo lipogenesis and prevents hepatic cell injury and death in cultured cells, liver organoids and mice. Pivotal clinical trials have confirmed that resmetirom markedly reduces liver fat content, ameliorates inflammatory injury, and reverses liver fibrosis while also effectively lowering atherogenic lipid levels. The medication has a favorable safety and tolerability profile. Based on these findings, resmetirom was approved by the US Food and Drug Administration (FDA) in 2024 and by the European Union in August 2025. Further directions in this field will pivot on investigating the cardiovascular benefits of resmetirom, exploring its use in combination with other drugs, and the elucidation of its underlying molecular mechanism networks. This article reviews the pharmacological and clinical evidence regarding the treatment of MASH with resmetirom published by April 2026, with the aim to expanding the pharmacological profile of resmetirom and promoting the development of THRB agonism-based anti-MASH pharmacotherapies.
Trivalent chromium is an essential trace element involved in carbohydrate and lipid metabolism. The widespread global prevalence of metabolic syndrome and its close association with cardiovascular diseases and type 2 diabetes mellitus have increased scientific interest in the potential metabolic effects of chromium. However, currently available evidence regarding its clinical significance remains inconsistent. This narrative review describes the role of trivalent chromium in the context of metabolic syndrome. A systematic literature search was conducted in the Scopus and Web of Science databases for studies published between 2015 and 2025. The review included randomized controlled trials, observational studies, experimental studies, systematic reviews, and meta-analyses that investigated chromium intake, supplementation, or the association between chromium levels and components of metabolic syndrome. The reviewed studies reported heterogeneous findings regarding the effects of trivalent chromium on components of metabolic syndrome. While some studies demonstrated improvements in glucose metabolism, insulin sensitivity, and lipid profiles, other studies reported no clear or statistically significant effects. The inconsistency of results has been attributed to differences in study design, studied populations, types and dosages of chromium supplementation, and duration of interventions. The lack of uniform research methodologies, limited sample sizes, and the absence of standardized protocols for chromium supplementation hinder the comparability of results. In addition, the heterogeneity of the studied populations limits the reliability of the available data. Available evidence does not support the widespread clinical use of trivalent chromium. Therefore, further large-scale studies are required to determine its efficacy and safety.
Tuberculosis (TB) remains a leading infectious cause of morbidity and mortality worldwide, and major diagnostic and therapeutic challenges persist despite advances in microbiologic and molecular testing. Over the past decade, molecular imaging, especially with FDG PET/CT, has transformed our understanding of TB pathogenesis, the spectrum of early and subclinical disease, mechanisms of dissemination, and treatment response. This review synthesizes key recent developments in TB imaging, focusing on studies published since prior Seminars in Nuclear Medicine reviews. New non-human primate and human PET/CT data provide unprecedented insight into the spatial and temporal evolution of granulomas, demonstrating highly localized microanatomic seeding, bronchogenic spread pathways, and heterogeneous lesion biology that strongly influence treatment outcomes. Imaging studies in asymptomatic individuals reveal that metabolically active subclinical TB is common and strongly predictive of future progression, redefining the spectrum of latent infection. In treatment monitoring, FDG PET/CT consistently outperforms conventional microbiologic biomarkers, correlating with lesion-level sterilization and identifying patients at risk for relapse, particularly when persistent metabolic activity remains at the end of therapy. The introduction of emerging tracers, such as integrin-targeted probes, offers complementary characterization of granuloma angiogenesis, immune microenvironments, and host-pathogen dynamics beyond glucose metabolism. Future priorities include the development of TB-specific radiotracers, the integration of PET with advanced computational modeling and AI-based quantification, and the translation of imaging biomarkers into individualized treatment strategies and drug-development pipelines. Collectively, these advances position molecular imaging as a central tool in elucidating TB biology and accelerating progress toward improved diagnostic, therapeutic, and prevention strategies.
Ferroptosis and pyroptosis are two distinct forms of regulated cell death that play crucial roles in cancer, neurodegeneration, and inflammatory diseases. Ferroptosis is characterised by iron-dependent lipid peroxidation, while pyroptosis is an inflammatory cell death mediated by gasdermin proteins. Recent studies reveal extensive crosstalk between these pathways. This review establishes the first hierarchical framework coupling the autophagy bridge function (ferritinophagy-mitophagy-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis) with the p53/signal transducer and activator of transcription 3 (STAT3)/Nuclear factor erythroid 2-related factor 2 (NRF2) transcriptional hub, creating a unified decision-making network absent in prior reviews. Crosstalk mechanisms include the reactive oxygen species (ROS)-NOD-like receptor protein 3 (NLRP3) positive feedback loop, caspase cross-activation, and iron metabolism-inflammasome integration. Preclinically, the transferrin-targeted nanosystem Tf-LipoMof@PL increased intratumoral iron/ROS 3-5-fold, inducing robust antitumour immunity, while Ginsenoside Rh3 suppressed colorectal cancer growth in vivo via STAT3/p53/NRF2-mediated dual death induction. We critically address STAT3's paradoxical roles-promoting Gasdermin E (GSDME)-mediated pyroptosis in oesophageal cancer while suppressing NLRP3 via suppressor of cytokine signalling 3 (SOCS3) feedback in acute respiratory distress syndrome (ARDS)-highlighting cell type-specific feedback architectures that dictate phenotypic outcomes. For therapeutic translation, we propose a Translational Priority Matrix ranking nanodelivery systems (Tf-LipoMof@PL) and dual-function small molecules (N6F11) as the highest priority for intrahepatic cholangiocarcinoma (iCCA)/triple-negative breast cancer (TNBC), while deprioritising metal photosensitizers pending resolution of cardiac retention toxicity (0.8 μg/g myocardium in Good Laboratory Practice (GLP) studies). The "registration gap" stems from iron burst-release (> 80% within 30 min) and species-specific biomarker failures. We advocate replacing murine malondialdehyde (MDA)/glutathione (GSH) ratios with human-anchored metrics (ferritin heavy chain 1 (FTH1)/solute carrier family 40 member 1 (SLC40A1) expression, serum ferritin) and propose a "Cross-Death AI Platform" integrating network pharmacology (OmniPath/STRING), GraphSAGE deep learning (AlphaFold2 structures), and organoid validation to stratify patients and predict optimal drug combinations. By resolving spatiotemporal heterogeneity and implementing AI-guided precision medicine, we can transform multi-target interventions from empirical strategies into rational, patient-specific regimens, bridging the gap between preclinical promise and clinical success in cancers and neurodegenerative diseases.