Expert Opinion on Therapeutic Targets最新文献

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) remains a formidable global health challenge, responsible for severe infections with unacceptably high mortality rates. Conventional antibiotics, though essential, face growing limitations due to resistance, poor penetration into biofilms, and inability to eliminate intracellular reservoirs. These shortcomings underscore the urgent need to explore MRSA-specific targets, including toxin secretion, quorum sensing, biofilm formation and efflux pumps in the design of intelligent antibiotic delivery systems. Nanocarriers provide an ideal platform to address these gaps by enhancing drug stability, penetration, and site-specific delivery, while enabling the co-administration of antibiotics with anti-virulence agents at otherwise inaccessible infection sites.

Areas covered: This review discusses emerging MRSA therapeutic targets, cell wall/membrane synthesis, quorum sensing, biofilms, virulence factors, and efflux pumps, and how nanocarrier-based systems have been engineered to exploit them. Advances from 2015-2025 are analyzed, highlighting nano-enabled strategies that enhance antibiotic efficacy, neutralize toxins, disrupt biofilms, and achieve high drug accumulation at infection foci.

Expert opinion: Targeting MRSA's virulence pathways through nanocarrier systems offers a paradigm shift beyond traditional antibiotics. The next decade will require not only optimization and mechanistic validation but also innovative material design, scalable manufacturing, and integration into clinical practice to realize the promise of nanocarrier-enabled anti-MRSA therapies.

Introduction: Type 1 diabetes (T1D) results from a destructive dialog between stressed pancreatic beta-cells and immune system. While current disease-modifying approaches targeting these processes are being developed and tested, microRNAs have emerged as a molecular interface connecting both sides of islet autoimmunity.

Areas covered: Specific miRNAs orchestrate beta-cell stress adaptation, immune activation, and intercellular communication, thus shaping disease trajectory and progression across stages. Recent discoveries identified distinct miRNA networks as ER-stress modulators and/or immune amplifiers and key regulators of beta-cell fate and circulating signals of ongoing inflammation.

Expert opinion: The clinical translation of these insights remains hindered by limited access to human tissues, inconsistent candidate validation, and lack of delivery systems capable of targeting pancreatic beta-cells. Bridging mechanistic understanding with advanced delivery systems may transform miRNAs both as biomarkers and active therapeutic agents, opening a path toward precision interventions in T1D.

Introduction: Skin cancer is one of the most prevalent types of cancer and has shown an upward trend recently. Among various types, melanoma skin cancer is known to be the most dangerous, exhibiting resistance to treatment, and is also prone to metastasis. Targeted and immunotherapeutic approaches, despite their potential, exhibit limitations. Recently, the research focus has shifted to various neurotransmitter-mediated pathways acting as a key mediator between tumor development and neuronal signaling. Among them, CHRM1 has garnered traction as a target that supports tumor growth and proliferation in skin cancer.

Areas covered: This review aims to address the role of acetylcholine-mediated interaction between keratinocytes and melanocytes for its implications in skin cancer. It has a special focus on CHRM1 as a central mediator influencing key survival and growth pathways linked to cholinergic input. It functions in a context-dependent manner, indicating its role as a diagnostic marker and a therapeutic target.

Expert opinion: Targeting CHRM1 represents a novel approach toward the treatment of skin cancer. The future advances in targeted delivery and rational drug combinations with existing therapies will be of critical significance against therapy resistance and opening the way for newer therapies.

Introduction: Calcified aortic valve disease (CAVD) imposes a severe global health burden, and there is currently no effective pharmacotherapy, which urgently requires a new understanding of pathophysiology to guide treatment.

Areas covered: This review systematically evaluates the epidemiological association and common mechanistic pathways between metabolic diseases and aortic valve calcification (AVC) through the proposed 'calcification-metabolic axis' framework. We conducted a comprehensive literature search, covering the PubMed database up to December 2025, with a focus on studies related to CAVD, metabolism, inflammation, and calcification signaling.

Expert opinion: Future management strategies must transition toward early, multi-disease co-governance strategies. At the same time, targeted drugs will be developed for specific pathways on this axis, surpassing the current treatment status of relying solely on valve replacement surgery.

Introduction: Gastric cancer remains a leading cause of cancer mortality due to late diagnosis, aggressive progression, and limited treatment response. Nanomedicine offers promising avenues to exploit molecular targets and improve therapeutic precision. Engineered nanoparticles with tunable physicochemical properties enable targeted delivery, enhanced bioavailability, and deeper tumor penetration. Understanding key molecular drivers of gastric cancer is essential for designing effective nanotherapeutic strategies.

Areas covered: This review summarizes major molecular targets relevant to nanomedicine development in gastric cancer, including HER2, VEGF/VEGFR, immune checkpoints, and tumor microenvironmental components. Advances in lipid-based, polymeric, and inorganic nanocarriers are discussed with emphasis on ligand-mediated targeting, overcoming drug resistance, modulating intracellular trafficking, and exploiting tumor-specific biomarkers. Progress in nanotechnology-enabled imaging, early detection platforms, and multifunctional theranostic systems that combine diagnosis and therapy is also highlighted. Key preclinical and emerging clinical findings are reviewed to illustrate translational progress and current limitations.

Expert opinion: Nanomedicine holds strong potential to transform gastric cancer therapy through selective, target-driven interventions. However, successful translation requires better molecular stratification, deeper insight into nano - bio interactions, standardized toxicity evaluation, and scalable manufacturing. Integrating genomics, biomarkers, and AI-driven design will be crucial for developing nanotherapeutics that address specific molecular vulnerabilities in gastric cancer.

Introduction: Up to 50% of adults with major depressive disorder (MDD) fail to achieve remission after two or more monoaminergic antidepressants and meet criteria for treatment-resistant depression (TRD). Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan represent the first glutamatergic treatments to exhibit rapid and robust efficacy in persons with TRD, yet their precise mechanisms remain unclear.

Areas covered: Herein, we amplify an existing hypothesis and integrate preclinical, pharmacological, and clinical evidence implicating elevated tonic N-methyl-D-aspartate (NMDA) receptor currents, mediated predominantly by NR2C/D subunits, in the pathophysiology of TRD. We review in vivo proton magnetic resonance spectroscopy and electrophysiology studies that document sustained ambient-glutamate signaling in key limbic regions. We then synthesize mechanistic data on ketamine's dual pore-trapping and hydrophobic lateral-site binding, esketamine's preferential NR2D blockade, and dextromethorphan's pH-enhanced NR2C selectivity.

Expert opinion: Selective dampening of NR2C/D-mediated tonic currents underlie rapid and sustained antidepressant effects of ketamine, esketamine, and dextromethorphan. Separately, ketamine and esketamine's affinity for NR2A/B subunits may constitute the core mechanism driving the dissociative effects which are not observed with dextromethorphan. Future drug discovery should emphasize subunit-biased ligands and allosteric modulators, guided by advanced receptor structural models and translational biomarkers, to enhance antidepressant efficacy and concurrently improve tolerability.

Introduction: Multiple myeloma (MM) is a plasma cell malignancy characterized by frequent relapse and resistance to therapy. Caveolin-1 (Cav-1), a scaffolding protein that forms plasma membrane caveolae, has been demonstrated to regulate key processes including cell signaling, metabolism, autophagy, and interactions with the bone marrow microenvironment.

Areas covered: This review outlines Cav-1's role in MM progression and therapy resistance, including its effects on cell survival, adhesion, and communication with the bone marrow environment. Preclinical approaches to target Cav-1, such as small molecules, peptides, RNA-based methods, CRISPR, and tumor-specific delivery, are summarized, including combination with proteasome inhibitors. Challenges for clinical translation, such as the lack of selective inhibitors and possible toxicity, are also discussed.

Expert opinion: Cav-1 is a context-dependent therapeutic vulnerability in MM. Blocking Cav-1 can restore drug sensitivity, reduce protection from the bone marrow environment, and improve immune killing of tumor cells. Given the multifaceted nature of Cav-1 and its prevalence in normal tissues, the development of selective or tumor-targeted delivery mechanisms is imperative. New strategies, including inhibitors and nanoparticle delivery, combined with biomarker-guided patient selection, may offer safe and effective targeting of Cav-1 and support combination treatments for resistant MM.

Background: Conversion of cholesterol into bile acids is a central pathway for cholesterol disposal, which was mainly controlled by cholesterol 7alpha-hydroxylase (Cyp7a1). In present study, we aimed to investigate the effect and the potential underlying mechanism of microRNA-96 (miR-96) on atherosclerosis development.

Research design and methods: The anti-atherosclerosis effects of a miR-96 inhibitor (miR-96i) were evaluated using ApoE KO mice fed a high-fat diet, which was treated with miR-96i for 8 weeks. Then the regulatory mechanism was revealed and validated by RNA-seq transcriptomics, quantitative PCR and western blotting analyses in hepatic cells.

Results: The authors identified that miR-96i significantly decreased serum cholesterol and bile acid levels and attenuated arterial plaque in mice. We further revealed that miR-96 regulated Cyp7a1 via a FOXO1-involved indirect pathway, in which miR-96 directly modulated FOXO1 in a posttranscriptional manner. A coordinated regulatory effect of miR-96 and miR-185 on FOXO1 was also observed. The full spectrum of mechanisms underlying the antiatherosclerotic activity beside miR-96-FOXO1-CYP7A1 axis remains to be elucidated.

Conclusions: This study provides convincing evidence for the pivotal role of miR-96 in FOXO1 modulation and CYP7A1-involved cholesterol-bile acid metabolism, suggesting that miR-96 is a novel therapeutic target for the discovery and development of drugs against ACVD.