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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.

Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

Despite the ever‐increasing number of available options for the treatment of epilepsies and the remarkable advances on the understanding of their pathophysiology, the proportion of refractory patients has remained approximately unmodified during the last 100 years. How efficient are we translating positive outcomes from basic research to clinical trials and/or the clinical scenario? It is possible that fresh thinking and exploration of new paradigms are required to arrive at truly novel therapeutic solutions, as seemingly proven by recently approved first‐in‐class antiseizure medications and drug candidates undergoing late clinical trials. Here, the author discusses some approximations in line with the network pharmacology philosophy, which may result in highly innovative (and, hopefully, safer and/or more efficacious) medications for the control of seizures, as embodied with some recent examples in the field, namely tailored multi‐target agents and low‐affinity ligands.

Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90–95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed.

It is essential to acknowledge the efforts made thus far to manage or eliminate various disease burden faced by humankind. However, the rising global trends of the socalled incurable diseases continue to put pressure on Pharma industries and other drug discovery platforms. In the past, drugs with more than one target were deemed as undesirable options with interest being on the one-drug-single target. Despite the successes of the singletarget drugs, it is currently beyond doubt that these drugs have limited efficacy against complex diseases in which the pathogenesis is dependent on a set of biochemical events and several bioreceptors operating concomitantly. Different approaches have thus been proposed to come up with effective drugs to combat even the complex diseases. In the past, the focus was on producing drugs from screening plant compounds; today, we talk about combination therapy and multi-targeting drugs. The multi-target drugs have recently attracted much attention as promising tools to fight against most challenging diseases, and thus a new research focus area. This review will discuss the potential impact of multi-target drug approach on various complex diseases with focus on malaria, tuberculosis (TB), diabetes and neurodegenerative diseases as the main representatives of multifactorial diseases. We will also discuss alternative ideas to solve the current problems bearing in mind the fourth industrial revolution on drug discovery

Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.

In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

Alzheimer’s disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N -methyl- d -aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer’s symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.

Epilepsy is a chronic neurological disorder characterized by abnormal neuronal discharge, leading to recurrent and unpredictable disruptions in brain function. Despite over 30 antiepileptic drugs (AEDs), 30% of patients develop drug-resistant epilepsy, requiring combination therapy. This review explores epilepsy’s pathogenesis, including neuronal hyperexcitability, neurotransmitter imbalances, and ion channel dysfunction, alongside genetic, inflammatory, immune, and oxidative stress factors. AEDs are classified by mechanisms like voltage-gated ion channel modulation and GABA/glutamate regulation, tracing their evolution from traditional (e.g., phenobarbital) to modern therapies (e.g., lamotrigine). Combination therapy, using complementary mechanisms (e.g., lacosamide with levetiracetam), enhances efficacy but poses risks like drug interactions and cognitive impairment. Integrating molecular biology and pharmacology advances, this review highlights the need for rational drug selection and individualized strategies to improve epilepsy treatment outcomes and patient quality of life. Future directions include personalized treatments, optimized dosage forms, novel drug targets, and multi-target drugs.

Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D2 receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of α7 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds.