搜索结果：Drug metabolism reviews

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.

Fatty acids (FAs) are vital biomolecules that serve not only as energy substrates but also as bioactive molecules, moieties of other lipids such as phospholipids and triglycerides, structural components of membranes, and precursors to other bioactive molecules. Environmental pollutants, are ubiquitous across environmental, wildlife, and human systems and disrupt FA homeostasis by targeting FA receptors and their associated metabolic networks. Although pollutant-induced disruption of FA metabolism is increasingly recognized, existing studies and reviews have often focused on individual pollutant classes, single receptors, or isolated metabolic processes, which has limited an integrated understanding of how chemically diverse pollutants converge on shared FA metabolic programs. This review provides a cross-pollutant synthesis of mechanistic insights into pollutant-induced disturbances in FA metabolism, focusing on receptor-mediated FA synthesis, oxidation, transport, storage, and utilization for the synthesis of other lipids. We review how pollutants interact with FA receptors and modulate downstream metabolic pathways, thereby altering the levels of FAs and other metabolites and contributing to toxic effects in multiple tissues. This review discusses several receptor-mediated signaling cascades and downstream metabolic pathways that drive pollutant-induced FA metabolic reprogramming and subsequent lipid accumulation. By delineating the pollutant-receptor-metabolite axis, this review provides a unifying framework for understanding how environmental pollutants across major classes drive metabolic reprogramming and for identifying potential intervention targets to mitigate their associated toxicity.

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.

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.

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).

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.

In the era of precision medicine, dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is the standard strategy for patients after percutaneous coronary intervention (PCI). Clopidogrel, as a widely used representative drug, has its efficacy significantly influenced by CYP2C19 genetic polymorphisms, leading to poor metabolism in some patients, insufficient exposure to active metabolites, and increased risk of ischemic events. In theory, CYP2C19 genotyping to guide individualized antiplatelet therapy could help optimize the clinical selection of P2Y12 inhibitors and improve prognosis. However, current evidence and guidelines do not support its use as a routine test for post-PCI patients, reflecting multiple challenges in clinical translation. From the perspective of precision medicine, this article systematically reviews the main problems and clinical application dilemmas of CYP2C19 genotyping in guiding clopidogrel therapy, including controversies and uncertainties in randomized controlled trials (RCTs) evidence, neglect of rare alleles, complexity of metabolism regulated by polygenic and clinical factors, and limited predictive value for low platelet reactivity. Finally, this paper prospects future research directions and clinical translation prospects, aiming to provide a theoretical reference for promoting individualized antiplatelet therapy and balancing thrombosis and bleeding risks.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are foundational therapies for type 2 diabetes and obesity. Beyond established cardiometabolic benefits, GLP-1 RAs' associations with noncardiometabolic outcomes remain uncertain. To evaluate the associations between GLP-1 RAs and noncardiometabolic outcomes, and to appraise the certainty and credibility of the supporting evidence. A systematic search of PubMed, Web of Science, Embase, Scopus, and the Cochrane Database of Systematic Reviews was conducted from database inception to January 15, 2026. Eligible studies were systematic reviews with meta-analyses of randomized clinical trials evaluating GLP-1 RAs and outcomes beyond glycemic control, weight management, and major cardiorenal end points. This umbrella review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. For each eligible meta-analysis, relevant data were extracted by 2 independent reviewers at both the meta-analysis level and individual study level. Data were reanalyzed using random-effects models to estimate odds ratios (ORs) and 95% CIs. The primary outcomes were noncardiometabolic outcomes across gastrointestinal, adverse event (AE), cancer, fracture, respiratory, neurologic, psychiatric, hepatic, and endocrine domains. Methodological quality was appraised via AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews). Evidence certainty was categorized using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework and prespecified credibility criteria. A total of 60 meta-analyses representing 116 unique adverse health outcomes were included, comprising 1751 randomized clinical trials and 3 580 616 participants. The study populations primarily involved people with type 2 diabetes (43 [71.7%]) and obesity (20 [33.3%]), with follow-up durations ranging from 3 months to 5.4 years or longer. The most consistent signals were for gastrointestinal AEs, with higher odds of nausea (OR, 2.47 [95% CI, 1.84-3.34]; GRADE: high quality of evidence), vomiting (OR, 2.78 [95% CI, 1.91-4.06]; GRADE: moderate quality of evidence), and diarrhea (OR, 1.94 [95% CI, 1.52-2.49]; GRADE: high quality of evidence), although between-study heterogeneity and 95% prediction intervals suggested residual uncertainty. Infection-related outcomes suggested possible protective associations, particularly for serious infections (OR, 0.89 [95% CI, 0.87-0.92]; GRADE: high quality of evidence), and a suggestive association was observed for incident respiratory disease (OR, 0.85 [95% CI, 0.80-0.92]). Other outcomes, including gastrointestinal disease and biliary events (eg, gallbladder or biliary disease: OR, 1.34 [95% CI, 1.16-1.55]), did not meet stringent credibility thresholds and should be considered exploratory. In this umbrella review of meta-analyses, evidence for most noncardiometabolic outcomes associated with GLP-1 RAs was of lower certainty. Potential safety signals were observed for gastrointestinal AEs, while suggested protective associations with respiratory diseases and serious infections require further confirmation.

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.

Targeted therapy for BRAF-mutant melanoma induces metabolic reprogramming, which drives the development of drug resistance. Studies indicate that following treatment with BRAF inhibitors and/or MEK inhibitors, melanoma cells alter metabolic pathways by modifying various regulatory factors. These adaptations include increased lactate accumulation, enhanced oxidative phosphorylation, elevated glutamine utilization via the tricarboxylic acid cycle, activation of the kynurenine pathway and increased fatty acid synthesis. Collectively, these alterations reshape the tumor microenvironment, suppress ferroptosis and activate alternative signaling pathways, thereby conferring resistance to targeted therapy. This paper systematically reviews the mechanisms underlying therapy-induced metabolic reprogramming in BRAF-mutant melanoma and explores potential combinatorial strategies that target these metabolic vulnerabilities alongside established melanoma therapies. Key metabolic targets with promising therapeutic potential identified include lysine-specific demethylase 1, oxidative phosphorylation components, phosphoglycerate dehydrogenase, indoleamine 2,3-dioxygenase 1 and lipid metabolism enzymes such as fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme a reductase.

Primary liver cancer (PLC) is among the most common malignant tumors of the digestive tract, with high incidence and mortality. Hepatocellular carcinoma (HCC) the predominant PLC form has complex pathogenesis. Traditional Chinese medicine (TCM) has gained widespread use as supportive treatment, demonstrating clear efficacy in HCC management. This article summarizes signaling pathways regulating ferroptosis in HCC cells and systematically reviews current research on pathway modulation by TCM active constituents and compound formulas, emphasizing their cytotoxic effects. HCC cellular survival strategies that evade ferroptosis, including hepatic stellate cell-mediated protective mechanisms, are discussed. Clinical limitations of ferroptosis-based treatments and potential solutions are addressed. A comprehensive literature search using PubMed, Embase, Web of Science, and Scopus examined signaling pathways in TCM-mediated ferroptosis in HCC cells. Search terms included "hepatocellular carcinoma," "ferroptosis," "signaling pathway," "traditional Chinese medicine," "TCM monomer," "TCM formula," and "TCM extract," limited to studies from January 2021 to October 2025. Thirty-nine studies were identified: 33 on TCM active ingredients, 1 on TCM extract, and 5 on herbal formulas. TCM active ingredients and formulas promote ferroptosis in HCC cells through modulation of signaling pathways. Pathway modulation inhibits HCC cell proliferation, invasion, and metastasis; promotes apoptosis; increases chemotherapeutic sensitivity; improves glucose metabolism; and reduces drug resistance. TCM can induce ferroptosis in HCC cells through multiple pathways, targets, and mechanisms,highlighting its therapeutic advantages and providing guidance for developing novel ferroptosis inducers.

Rheumatoid arthritis (RA) progresses through distinct pathophysiological states, transitioning from acute inflammatory phases with largely reversible tissue damage to chronic destructive stages characterized by irreversible structural alterations. Current therapeutic approaches largely employ uniform interventions without accounting for this disease heterogeneity, potentially compromising treatment efficacy. Dysregulated reactive oxygen species metabolism represents a mechanistic thread connecting RA stages. Acute inflammation is characterized by intense oxidative bursts, whereas chronic RA exhibits persistent oxidative stress, establishing a stage-dependent rationale for enzyme-based intervention. However, natural antioxidant enzymes are rapidly inactivated within the harsh inflammatory microenvironment, which is defined by acidic conditions and elevated proteolytic activity. Nanozymes are nanomaterials with enzyme-like catalytic activities, which overcome these limitations through enhanced environmental stability, tunable catalytic activity, and multifunctional integration. In contrast to prior nanozyme reviews that primarily organized discussions by material types or catalytic mechanisms, this review adopts a stage-oriented framework that aligns therapeutic strategies with the temporal evolution of RA pathophysiology. During acute inflammatory phases, nanozyme platforms integrate catalytic performance optimization, targeted delivery mechanisms, and synergistic anti-inflammatory interventions to rapidly neutralize oxidative stress and disrupt inflammatory cascades before irreversible damage occurs. In chronic destructive phases, therapeutic approaches combine sustained catalytic activity, precision targeting of established pathological structures, and multifunctional integration to concurrently suppress residual inflammation and promote tissue regeneration. This review compares nanozyme therapeutics with established RA treatments, including disease-modifying antirheumatic drugs and biological agents, to clarify their potential clinical positioning. Key challenges for clinical translation include long-term safety characterization; pharmacokinetic evaluation, particularly for intra-articular delivery; regulatory pathway development; and manufacturing scalability. Overall, this review establishes a stage-oriented nanozyme therapeutic framework aligned with RA progression patterns and provides translational guidance for developing nanozyme therapeutics tailored to individual pathological characteristics in RA management.

Sulfonamides (SAs) are frequently detected in natural water bodies, sediments, and wastewater treatment plants (WWTPs). Their persistence in the environment induces the generation and dissemination of antibiotic resistance genes (ARGs) as well as drug-resistant bacteria, posing threats to ecosystems and public health. Current processes are insufficient for the removal of SAs. This paper reviews the recent research progress in SAs in terms of the occurrence concentrations, biological toxicity, and induction of resistance gene transfer, as well as our preliminary work on the degradation technology and mechanisms of SAs. Through the review, this paper summarizes the pollution status, hazards, biodegradation processes and key influencing factors of SAs, clarifies the roles of biological community interactions, microbial co-metabolism, eukaryotic enzymatic degradation, and interactions between gut microbiota and the host in the degradation of SAs and horizontal transfer control process of ARGs, and outlines representative degradation pathways, degradation kinetics, and related research methods. Furthermore, this paper makes an outlook on the future research directions from the aspects of innovative combination process, multi-factor synergistic influencing mechanisms, and mutually beneficial cooperation between eukaryotes and their microbial communities, aiming to provide insights for deciphering the degradation mechanisms of SAs and formulating pollution control measures. 磺胺类抗生素(sulfonamides, SAs)在自然水体、沉积物和污水处理厂中检出率高，长期存在会诱导抗性基因和耐药菌的产生和传播，对生态系统和公共健康构成威胁。我国城镇污水处理厂现有工艺难以实现对SAs的有效削减。本文基于近年来国内外学者在SAs检出浓度、生物毒性、诱导抗性基因转移等方面的研究进展，结合本课题组开展的SAs降解技术与机制研究方面的工作，总结了污水中SAs的污染现状和危害、生物降解工艺、关键影响因素，阐明了生物群落协作、微生物共代谢、真核生物酶解、肠道菌群与宿主互作等在SAs降解和抗性基因(antibiotic resistance genes, ARGs)水平转移控制过程中的作用原理，梳理了代表性SAs的降解路径、降解动力学和相关研究方法，并从组合工艺创新、多因素协同影响机制、真核生物及其微生物组互利协作等方面对未来研究方向进行了展望，为SAs降解机理的深入研究和污染治理提供参考。.

Epilepsy remains a complex neurological disorder with a significant proportion of patients exhibiting drug-resistant epilepsy, underscoring the need for novel therapeutic solutions. Despite the availability of numerous antiepileptic drugs, the γ-aminobutyric acid (GABA) system, particularly the GABAA receptor, remains one of the most validated targets for anticonvulsant drug design due to its central role in inhibitory neurotransmission. This review provides a comprehensive analysis of next-generation GABAA receptor modulators, exploring their pharmacological mechanisms, receptor subtype selectivity, and structure-activity relationships. Various heterocyclic scaffolds, including benzodiazepines, imidazoles, thiazoles, oxadiazoles, and bicyclic or fused ring systems, exhibit promising anticonvulsant properties with selective receptor binding and reduced side effects. A systematic literature search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines using PubMed, Scopus, and Web of Science databases from 2018 to 2024. Recent advancements in molecular design, docking studies, and in vivo evaluations highlight how specific molecular modifications enhance receptor affinity, blood-brain barrier permeability, and metabolic stability. Key findings highlight the structural features that enhance receptor affinity, pharmacokinetics, and efficacy. Future research must concentrate on designing these heterocyclic frameworks more efficiently while evaluating their selective receptor binding and performing clinical research to develop advanced anticonvulsant medicines.

Renal cell carcinoma (RCC) is a type of solid tumor with one of the highest incidences among urinary system malignancies, and its incidence continues to increase worldwide. The PI3K-AKT-mTOR signaling pathway, as a central signaling hub that regulates biological processes such as cell survival, proliferation, metabolism, and metastasis, often exhibits abnormal and sustained activation during the pathological progression of RCC. Dysregulation of this pathway synergistically promotes tumor progression through multiple mechanisms, including enhancing the survival and clonal expansion of tumor cells, inducing angiogenesis, driving metabolic reprogramming of the tumor microenvironment, and mediating treatment resistance. These pathological changes are closely associated with poor patient prognosis. Given the central role of the PI3K-AKT-mTOR signaling pathway in the pathogenesis of RCC, it has become a key target for targeted therapeutic intervention. Although multiple small-molecule inhibitors targeting this pathway have demonstrated potential for inhibiting tumor growth in preclinical studies and early-phase clinical trials, their clinical application still faces numerous challenges. Against this backdrop, combination therapy strategies offer a new approach to overcome the limitations of single-agent therapy, not only enhancing treatment efficacy but also potentially reducing the risk of drug resistance. Notably, natural products and their derivatives, due to their low toxicity, ability to modulate multiple targets, and specific inhibitory effects on cancer stem cells, are regarded as promising sensitizers in combination therapy. This article systematically reviews the pathological features of RCC and current clinical treatment strategies, with a focus on exploring the molecular regulatory mechanisms of the PI3K-AKT-mTOR signaling pathway in tumor progression, while highlighting the latest research advances in small-molecule inhibitors targeting this pathway. Integrating preclinical mechanistic studies and relevant clinical trial data, the limitations of existing agents are analyzed, and potential optimization directions are proposed, aiming to provide theoretical support and practical references for the clinical translation of precision therapy for RCC and to promote the transformation of pathway-based combination therapy models into clinical applications.

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.