INTRODUCTION:The emergence of partial resistance to artemisinin-based therapies has intensified the search for antimalarial targets beyond classical kinases and proteases. Protein disulfide isomerases (PDIs) have emerged as attractive candidates due to their roles in endoplasmic reticulum (ER) oxidative folding, redox homeostasis, and survival under proteotoxic stress. Several Plasmodium falciparum PDI family members are essential during asexual blood stages and contribute to parasite transmission. AREAS COVERED:We summarize PfPDI architecture, catalytic and holdase functions, and their integration within the parasite ER folding network, highlighting structural divergence from human PDIs that may enable selective inhibition. We review PDI-directed chemotypes, including covalent active-site binders and non-covalent/allosteric modulators, and highlight the absence of PfPDI-selective probes with validated intracellular mechanisms. We further discuss approaches for target validation, including chemoproteomics, activity-based profiling, and chemical genetics, alongside medicinal chemistry considerations for achieving exposure to an intracellular ER target. Finally, we examine PfPDIs within a proteostasis-stress framework and discuss combination strategies with protein-damaging agents such as artemisinin derivatives. EXPERT OPINION:Progress will depend on structure-guided targeting of divergent non-catalytic surfaces, optimization of intracellular and ER exposure, and rigorous in-parasite target-engagement studies. PfPDI inhibitors are most likely to succeed as components of resistance-robust combination therapies.
INTRODUCTION:Axial spondyloarthritis (SpA) is a chronic inflammatory rheumatism affecting predominantly the axial skeleton and frequently also the peripheral joints, often associated with specific extra-musculoskeletal manifestations. This complex disease is still poorly understood resulting in a lack of cure. While symptomatic treatments are available, preclinical models/analyses are needed to identify new therapeutic targets in order to improve axial SpA treatment. AREAS COVERED:We discussed strengths and weaknesses of preclinical models used to identify and validate emerging therapeutic targets. EXPERT OPINION:Progress in developing new therapies for axial SpA remains slow due to its biological complexity and limited understanding of early disease mechanisms. Current treatments mainly target downstream inflammation, contributing to persistent unmet needs and variable responses. Future progress will rely on more pathophysiologically relevant models, interdisciplinary approaches, and integration of insights from related diseases to accelerate personalized therapeutic development.
INTRODUCTION:Diabetic macular edema (DME) is a major cause of vision loss in diabetic retinopathy. Although anti-vascular endothelial growth factor (VEGF) therapy is the current standard treatment, many patients show incomplete responses, indicating the contribution of VEGF-independent mechanisms. Increasing evidence identifies interleukin-6 (IL-6) as a key mediator of inflammation, blood-retinal barrier disruption, and retinal vascular dysfunction in DME. AREAS COVERED:This review summarizes the biological functions and signaling pathways of IL-6 in DME and examines the clinical relevance of elevated intraocular IL-6 levels. We discuss the crosstalk between IL-6 and VEGF, review current evidence for IL-6-targeting agents, including tocilizumab and sarilumab, and evaluate their therapeutic potential, particularly in treatment-resistant DME. EXPERT OPINION:IL-6 acts as a central hub cytokine linking chronic inflammation, vascular permeability, and retinal microvascular injury. By modulating both VEGF-dependent and VEGF-independent pathways, IL-6 inhibition represents a promising therapeutic strategy for refractory DME. Although direct clinical evidence remains limited, advances in biomarker-guided patient selection, local drug delivery systems, and combination approaches with anti-VEGF therapy may facilitate the development of precision medicine for DME.
INTRODUCTION:Branched-chain keto acid dehydrogenase kinase (BCKDK) is a mitochondrial kinase that suppresses branched-chain amino acid (BCAA) oxidative catabolism by phosphorylating and inhibiting the branched-chain α-keto acid dehydrogenase complex. Beyond this canonical metabolic function, accumulating evidence indicates that aberrant BCKDK activation contributes to tumor metabolic rewiring, signaling adaptation, malignant progression and therapy resistance. AREAS COVERED:This review summarizes the regulatory position of BCKDK in BCAA catabolism, its context-dependent functions across tumor types, and recent progress in BCKDK inhibitor development. Although selected non-oncological studies are discussed to inform inhibitor mechanism, pharmacology and safety, this review focuses on the oncology relevance of BCKDK. Particular attention is given to the transition from early proof-of-concept inhibitors to BT2-derived allosteric compounds, Pfizer-developed clinical candidates, and emerging non-BT2 scaffolds or alternative binding regions. A PubMed search was conducted to identify relevant studies on BCKDK, BCAA metabolism, cancer progression and BCKDK-targeted inhibitors. EXPERT OPINION:BCKDK is unlikely to function as a universal pan-cancer target. Its therapeutic value will depend on identifying tumor contexts with true BCKDK dependency, especially those relying on BCKDK-driven metabolic adaptation or downstream signaling. For BCKDK inhibitors, future development should integrate biochemical potency with mechanism-aligned conformational effects, long-term pharmacological consequences and biomarker-supported patient stratification.
INTRODUCTION:Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling, rising right-ventricular afterload, and eventual maladaptation, which is a major determinant of prognosis. While established therapies mainly target vasoconstrictive pathways, recent development has shifted toward disease-modifying strategies that address remodeling, inflammation, and metabolic dysfunction in PH patients. AREAS COVERED:This Special Report summarizes selected breakthrough therapeutic targets in PH, focusing on mechanisms supported by strong causal rationale and evaluated in at least Phase II clinical testing. Covered pathways include bone morphogenetic proteins/activin signaling rebalancing, growth factor and kinase inhibition, zinc transport targeting, inflammatory and immune-directed approaches, and metabolic modulation. We emphasize translational relevance, current clinical status, and key challenges limiting broader implementation of these approaches. EXPERT OPINION:The next advance in PH treatment will depend not only on identifying effective targets but also on improving precision in their deployment. Three barriers are especially important: responder heterogeneity, incomplete benefit-risk stratification, and uncertainty about target engagement in vivo. Therefore, biomarker-guided enrichment, integrated safety profiling, and practical pharmacodynamic readouts should become central elements of trial design. In parallel, expansion of the therapeutic toolbox, including stress-sensing, adrenergic, senescence, and hypoxia-related pathways, may increase the likelihood of matching individual patients to effective disease-modifying therapy.
INTRODUCTION:B-cell lymphomas (BCLs) are the most prevalent group of hematologic cancers, encompassing various subtypes, each with a distinct clinical course shaped by cell of origin, genetics, and etiology. Recent advances in subtype-specific immunochemotherapy, targeted therapies, and cellular immunotherapy have improved outcomes for BCLs; nonetheless, some cases remain resistant to existing treatments. To address these resistant disease states, especially across multiple subtypes, the development of new universal targeted therapies could be transformative. AREAS COVERED:This review first highlights what distinguishes the PDPK1/RSK2 signaling axis, outlines its normal biological functions, and briefly examines its roles in solid tumors. It then narrows the focus to BCLs, supported by evidence from our research on pathway activation, functional dependence, prognostic value, and early-stage drug development. EXPERT OPINION:The PDPK1/RSK2 axis is activated in nearly all BCL subtypes and likely plays a significant role in disease development. This suggests the potential for treatments that work across subtypes, despite their genetic and phenotypic differences. Targeting a shared signaling pathway might help overcome resistance seen with traditional precision medicine and support the development of new therapies for rare disease subtypes. However, because current research remains preclinical, more work is necessary.
INTRODUCTION:Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional stress-response regulator that coordinates genome maintenance, redox signaling, RNA biology, and cellular metabolism. Its expression and subcellular localization further determine disease states and severity. The growing appreciation of its biological complexity and clinical relevance makes APE1/Ref-1 an increasingly attractive therapeutic target for redox-stress-related diseases. AREAS COVERED:In this review, we aim to consolidate information on the structural and mechanistic basis of APE1/Ref-1 redox and repair functions, while recognizing emerging evidence in DNA/RNA-forming G-quadruplex (rG4) biology, RNA metabolism, protein homeostasis, and mitochondrial function. We discuss mechanisms regulating APE1/Ref-1 expression, activity, and trafficking, which dynamically influence function in physiological and disease contexts. We specifically emphasize therapeutic strategies including redox-specific inhibition, endonuclease-targeted approaches, and genetic perturbations that result in distinct effects across disease models. EXPERT OPINION:Evolving understanding of APE1/Ref-1 biology has accelerated therapeutic development, particularly through redox-selective targeting strategies. Small-molecule inhibitors such as APX3330 and new-generation analogs like APX2009 and APX2014 have advanced into therapeutic applications spanning cancer, inflammatory disorders, and ocular diseases. Continued investigation into the context-dependent and multifunctional roles of APE1/Ref-1, together with the progression of mechanism-informed therapeutic design, is steadily strengthening the translational potential of APE1/Ref-1-directed therapies.
INTRODUCTION:In the era of precision medicine, targeting resistance mechanisms is a rational approach to optimize treatment management based on tumor molecular profiling, with the goal of improving clinical outcomes. However, the role of tailored strategies in the treatment algorithm of EGFR-mutated NSCLC remains incompletely defined. AREAS COVERED:This review provides an overview of resistance mechanisms to EGFR-targeted therapy. Acquired resistances include on-target alterations (EGFR C797S and other secondary kinase domain mutations), off-target pathways activation (MET or HER2 amplification, RAS-MAPK, oncogenic fusions), and neuroendocrine transformation to SCLC. Evidence from clinical and observational studies demonstrates activity of tailored therapies, such as EGFR plus MET inhibitors combinations. In parallel, mechanism-agnostic strategies, including bispecific antibodies and ADC have emerged as effective options in the post-osimertinib setting. EXPERT OPINION:Comprehensive molecular assessment through both tissue and liquid biopsy at EGFR-TKI progression is essential to identify actionable alterations and guide treatment decisions. When supported by Molecular Tumor Board discussion, biomarker-driven strategies could enable personalized treatment selection and provide effective chemotherapy-free options. Emergence of upfront combinations is reshaping the biological landscape of EGFR-TKI resistance, increasing the proportion of patients with unknown escape mechanisms and potentially affecting the feasibility of molecularly matched therapies in later lines.
BACKGROUND:Previous study showed the PARP inhibitor ABT-888 potentiates the cytotoxicity of 5-fluorouracil (5-FU) by inhibiting PARP1-mediated mismatch repair (MMR) pathway via MSH6 deregulation in MMR-proficient colorectal cancer stem cells (CRC-CSCs). Emerging evidence indicates 5-FU regulates O6 -methylguanine-DNA-methyltransferase (MGMT) activity, but the mechanistic basis of MGMT involvement in PARP1-mediated MMR pathway following 5-FU treatment remains complex and poorly defined. RESEARCH DESIGN AND METHODS:This study delineates the role of MGMT in 5-FU-induced MMR pathway activation and evaluates 5-FU+ABT-888 combination effects on MGMT modulation in CRC-CSCs. The molecular mechanism has been studied by using colocalization, western blot, co-immunoprecipitation, MGMT gene-knockdown, and molecular docking in in vitro, in silico, and ex vivo preclinical models. RESULTS:5-FU treatment induced PARylated-PARP1 in CRC-CSCs, promoting PARP1-MGMT-MSH6 interactions that activated MMR. ABT-888 inhibited PARylation in 5-FU-pre-exposed CSCs. Therefore, PARP1 could not physically interact with both MGMT and MSH6, and complete abolishment of MGMT and MSH6, and MMR protein downregulation were observed in combination treatment. MGMT silencing confirmed its critical role in PARP1-mediated MMR activation. Similar findings were obtained in in silico and ex vivo models. CONCLUSIONS:5-FU+ABT-888 enhanced CRC-CSCs death by inhibiting the PARP1-MGMT-MSH6 interaction and simultaneously inhibiting the MGMT-dependent PARP1-mediated MMR pathway in MMR-proficient CRC-CSCs.
INTRODUCTION:RGPR-p117 was identified as a transcription factor that binds to the TTGGC(N)6CC sequence in the promoter region of the regucalcin gene, a tumor suppressor. This article discusses the therapeutic potential of targeting RGPR-p117 in cancer cells. AREA COVERED:The cytoplasmic RGPR-p117 moves into the nucleus of cells. Once there, it enhances the transcription of several genes containing a TTGGC motif. Overexpression of RGPR-p117 suppresses the proliferation of cancerous cells and decreases the expression levels of proteins that promote their growth, such as Ras, PI3K, Akt, MAPK, and mTOR. It increases the tumor suppressors p53, Rb, and p21. RGPR-p117 also enhances the regucalcin gene expression, which can prevent and treat carcinogenesis. Increasing RGPR-p117 transcription activity may be a promising approach for gene therapy in cancer cells. EXPERT OPINION:Developing novel therapeutic agents that target the RGPR-p117 gene and applying gene therapy are significant and novel cancer treatment strategies. Targeting the RGPR-p117 nuclear translocation pathway may be a new way to suppress cancer. RGPR-p117 shows promise as an effective cancer therapy. However, all of these findings are from in vitro studies. Further in vivo studies and clinical trials are needed, as are solutions to problems, including cancer burden and the need for new targets.
INTRODUCTION:The search for actionable genetic targets in cancer has evolved substantially over the past decade. Earlier approaches were focused on single genes or individual molecular alterations, but this is insufficient to capture tumor complexity in vivo. Cancer is influenced not only by genomic changes but also by transcriptional plasticity, epigenetic regulation, protein activity, metabolic adaptation, and dynamic interactions with the tumor microenvironment. Consequently, bioinformatic target discovery has shifted toward integrative, systems-level models of tumor biology. AREAS COVERED:This article discusses the evolution of bioinformatic approaches for cancer target identification, underscoring key achievements and persistent challenges. Advances from 2018-2025 are analyzed, including multi-omics integration, single-cell sequencing, and functional genomics, which enhance the identification of context-dependent molecular vulnerabilities. Also, the role of machine learning in analyzing large-scale datasets to uncover potential therapeutic targets is discussed. EXPERT OPINION:Precision medicine now recognizes that genetic background alone is insufficient to define actionable targets. Factors such as cell type, tumor spatial context, environmental influences, clonal lineage and epigenetic state are vital. Current bioinformatic frameworks increasingly incorporate artificial intelligence, offer unprecedented opportunities to integrate these dimensions and refine target discovery.
INTRODUCTION:Atopic dermatitis (AD) is a chronic inflammatory skin disorder driven by Th2-related cytokines, including interleukin-4 (IL-4) and IL-13. Recent single-cell sequencing and proteomic studies have demonstrated that sustained immune activity can persist even after treatment with the anti-IL-4 receptor alpha antibody dupilumab. Thus, targeting C-C chemokine receptor 4 (CCR4), which is highly expressed by Th2 cells and drives their migration into the inflamed tissues such as skin in response CCL17 (TARC) and CCL22 (MDC), could be a promising therapeutic approach for the treatment of AD. AREAS COVERED:This review summarizes: 1) the role of CCR4 and its primary endogenous ligands CCL17 and CCL22 in AD pathobiology; 2) the molecular pharmacology and associated signaling pathways of CCR4; and 3) the current landscape of CCR4 inhibitors, including key challenges in their discovery/development. The implications of CCR4 pharmacology in the development of new therapeutic agents are also discussed. EXPERT OPINION:New insights into the function and molecular pharmacology of CCR4 have informed the discovery of molecules that target CCR4 directly (e.g. small-molecule allosteric inhibitors) as well as ones that target the CCL17/CCL22/CCR4 signaling axis broadly (e.g. neutraligands). Ongoing efforts to develop therapies targeting this pathway may yield new treatments for AD.
INTRODUCTION:Nuclear factor erythroid 2-related factor 1 (Nrf1, encoded by NFE2L1) plays a central role in maintaining cellular homeostasis, basal redox balance, and mitochondrial quality control and its function. Recent studies have revealed that Nrf1 assumes complex, even opposing, roles in functioning both as a tumor-suppressor and otherwise, also as an unconvincing driver of Hepatocellular carcinoma (HCC) progression through certain oncogenic pathways and redox stress adaptation. AREAS COVERED:This mini-review systematically outlines the molecular-cellular regulatory network of Nrf1 and further elucidates its functional divergence and synergy with Nrf2 (encoded by NFE2L2) in HCC. EXPERT OPINION:Research on Nrf1 in the field of HCC has evolved from describing its basic pathophysiological functions to a systematic analysis of its putative dual roles in tumor initiation and progression, its isoform specificity, complex regulatory networks, and therapeutic potentials. Targeting Nrf1 for hepatocellular carcinoma therapy is just facing multiple challenges. Future research priorities will focus on elucidating Nrf1 isoform specificity and post-translational modification profiles, developing a molecular classification system based on the Yin (Nrf1)-Yang (Nrf2) balance, and even non-equilibrium steady-states, and screening for Nrf1α/TCF11-targeting modulators or activators to stimulate homeostatic anti-cancer defense mechanisms.
INTRODUCTION:Cholestatic liver disease (CLD) is a group of hepatobiliary disorders characterized by impaired bile flow, leading to the accumulation of toxic bile acids (BAs) and progressive liver injury. The available pharmacotherapies are limited and often inadequate. AREAS COVERED:This review explores the therapeutic potential of BA-activated receptors, encompassing nuclear receptors and membrane-bound G protein-coupled receptors, in the context of CLD. A comprehensive search of the relevant literature was conducted by means of targeted searches of recent peer-reviewed studies focusing on preclinical and clinical studies of BA receptor modulators. The present study transcends a mere descriptive catalog, instead providing a balanced assessment of key signaling cascades. Moreover, the text undertakes a critical discussion of translational failures and safety concerns. The present study focuses on the examination of emerging therapeutic classes and experimental natural products, with particular emphasis on clinical feasibility and limitations. EXPERT OPINION:The failure of pan-FXR agonists signals a need for a paradigm shift. The present study puts forward a novel framework for the development of context-dependent, isoform-selective modulators. It is anticipated that a shift from pan‑FXR agonism to pathway‑selective modulation will occur within a five-year timeframe.
INTRODUCTION:Cardiac hypertrophy (CH) is a major contributor to cardiovascular disease (CVD), affecting millions worldwide. While initially an adaptive response, sustained hypertrophic stimuli lead to maladaptive outcomes, including heart failure (HF), contractile dysfunction, and ventricular remodeling. Key pathophysiological processes involve myocardial fibrosis, cardiomyocyte death, mitochondrial impairment and Ca2+ dysregulation. Despite available therapies, treatment of CH is symptomatic with no approved targeted options. Many interventions have only temporary benefits, may cause adverse hemodynamic effects, and involve procedural risks. AREAS COVERED:This review highlights TRP channels as emerging therapeutic targets in CH. TRP channels play pivotal roles in calcium (Ca2+) homeostasis and modulate apoptosis, cell proliferation, hypoxia adaptation, inflammation, and metabolic reprogramming, core drivers of cardiac remodeling. Pharmacological modulation of TRP activity may counter pathological hypertrophy by tuning hypertrophic signaling, mitigating fibrosis, and enhancing cardiac performance. Incorporating TRP-targeted strategies into treatment paradigms could help address the limitations of current therapies. EXPERT OPINION:We propose that TRP channel-based interventions with mechanistic insights, hold significant promise for precision management of CH. Many TRP subtypes remain uncharacterized, and their investigation could reveal new therapeutic aspects. Future research should prioritize mapping TRP-mediated pathways and validating their translational potential.
INTRODUCTION:Opioid use disorder (OUD) and chronic pain are major global health challenges. Although opioid therapies provide effective analgesia, long-term use is limited by safety concerns, dependence, and variable efficacy. Modulation of the endocannabinoid system (ECS) has emerged as a potential therapeutic strategy for pain management and opioid-related disorders. AREAS COVERED:This narrative review summarizes evidence on ECS-targeted interventions for OUD, chronic non-cancer pain, and cancer-related pain. Relevant literature was identified through PubMed using terms related to the ECS, cannabinoid receptors (CB1 and CB2), phytocannabinoids (Δ⁹-tetrahydrocannabinol [THC] and cannabidiol [CBD]), synthetic cannabinoids, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors, and opioid-cannabinoid interactions. Emphasis is placed on interactions between ECS and opioid signaling pathways and findings from preclinical and clinical studies evaluating efficacy and safety. EXPERT OPINION:This narrative review summarizes evidence on ECS-targeted interventions for OUD, chronic non-cancer pain, and cancer-related pain. Relevant literature was identified through PubMed using terms related to the ECS, cannabinoid receptors (CB1 and CB2), phytocannabinoids (Δ⁹-tetrahydrocannabinol [THC] and cannabidiol [CBD]), synthetic cannabinoids, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors, and opioid-cannabinoid interactions. Emphasis is placed on interactions between ECS and opioid signaling pathways and findings from preclinical and clinical studies evaluating efficacy and safety.
INTRODUCTION:Cardiovascular diseases (CVDs) pose a significant threat to the health of middle-aged and elderly people. They are widely recognized as a major public health concern. The sirtuin (SIRT) family comprises seven proteins (SIRT1-SIRT7), all of which contain a highly conserved nicotinamide adenine dinucleotide (NAD+)-binding catalytic domain. Notably, SIRT1 influences the development and progression of CVDs by regulating biological processes such as inflammation, immune responses, oxidative stress, and autophagy. AREAS COVERED:This review summarizes the biological functions of SIRT1 and its role in major cardiovascular conditions, with particular attention to cell-type-specific effects. It examines the preclinical efficacy of SIRT1 activators, such as resveratrol and SRT1720, and discusses challenges including dose dependency, specificity, and barriers to clinical translation. A comprehensive literature search (PubMed, Web of Science, Scopus; 2000-April 2026) was conducted to identify studies on SIRT1 in CVDs, with a focus on mechanistic insights and therapeutic relevance. EXPERT OPINION:We believe that developing highly specific SIRT1 activators, identifying predictive biomarkers, and elucidating tissue-selective regulatory mechanisms can amplify SIRT1's protective effects in cardiac diseases. Current and future clinical trials should establish the safety and efficacy of SIRT1-targeted therapies at the earliest possible stage.
