The growing burden of cardiometabolic and chronic inflammatory diseases has placed immense pressure on global health-care systems (Peake et al., 2025; Ren, Wang, Tate Raghubeer, 2024; Ren, Bi, et al., 2021; Ren et al., 2018; Y. Zhang et al., 2018). As our understanding of the underlying mechanisms continues to evolve, recent studies have unveiled novel and promising approaches, especially with regards to drug development, to tackle these challenges. In this special issue entitled 'Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases', we highlight key contributions grouped into four interrelated thematic areas that reflect the forefront of biomedical innovation: (1) inflammation and immune signalling in cardiometabolic and fibrotic diseases, (2) natural products and small molecule therapeutics, (3) metabolic reprogramming and mitochondrial therapeutics, and (4) emerging cell-based and receptor-targeted strategies. Chronic inflammation lies at the heart of many metabolic and cardiovascular disorders. The articles included in this section elucidate novel molecular pathways linking inflammation to disease progression, with implications for targeted therapy. A notable advance comes from Ding and colleagues who identified triptolidiol, a derivative of the natural product triptolide, as a selective and potent inhibitor of NLRP3 inflammasome activation. Triptolidiol acts by disrupting K63-specific ubiquitination and preventing NLRP3-NEK7 interaction, showcasing its promise in treating acute inflammatory syndromes such as lung injury and sepsis (Ding, Ning, et al., 2024). In atherosclerotic work from Liu and team, 5-HT2B receptor deficiency was shown to shift macrophage phenotypes towards an anti-inflammatory state through suppression of interferon signalling and inflammasome activation. This novel immunological angle uncovers serotonin signalling as a modifiable risk pathway in plaque development (Liu et al., 2024). Fulminant myocarditis is an acute and severe diffuse inflammatory disease of the heart with a high mortality rate (Shu et al., 2024). Wang's group have made milestone progress in its diagnosis and treatment, leading to significantly increased diagnostic efficiency and decreased mortality (Chinese Society of Cardiology et al., 2024; J. Wang et al., 2022; Xuan et al., 2025). Here, new immunomodulatory interventions in myocarditis are addressed with immunoglobulin therapy, which was found to modulate innate immune responses by targeting Plac8+ monocytes and S100a8+ neutrophils. Wen and colleagues demonstrate that the therapeutic benefit is likely mediated via ILT7–BST2 signalling, offering a multi-dimensional immune regulatory strategy rather than immunosuppressants (Wen et al., 2024). The concept of trained innate immunity is also gaining traction. A comprehensive review from Chen and coworkers illustrates how early-life and environmental risk factors induce long-lasting epigenetic and metabolic reprogramming of innate immune cells, potentially predisposing individuals to cardiovascular events despite risk factor modification later in life (Chen, Kang, et al., 2024). Targeting the Src–STAT3 axis in endothelial cells was another significant breakthrough. Based on research from Ding and associates, Src inhibition via dasatinib attenuated disturbed-flow-induced inflammation and plaque formation, implicating Piezo1–Src coupling as a mechanosensory hub in vascular disease (Ding, Jiang, et al., 2024). Meanwhile, IN-115314, a novel small molecule, was investigated for its pharmacokinetic and pharmacodynamic properties, which rival those of established agents in preclinical models, providing a new candidate for diseases with inflammatory underpinnings through inhibiting JAK–STAT signalling (Ahn et al., 2025). Finally, studies from Jiang and team on TRPC6 and YAP signalling help extend immune regulation into fibrotic contexts. TRPC6 activation suppresses hepatic stellate cell-mediated liver fibrosis through CREB signalling (Jiang et al., 2025), while diminished nuclear-localised beta-adrenoceptor signalling promotes kidney fibrosis via the PKA-YAP axis, based on work presented by Xiang et al. (2024). These findings reinforce the cross-organ relevance of inflammation. The repositioning of natural compounds as precision therapeutics continues to gain momentum. Moving beyond empirical usage, several studies have uncovered defined molecular targets and mechanisms of action for phytochemicals. Berberine demonstrated therapeutic efficacy in diabetic cardiomyopathy by enhancing SIRT3-mediated lipophagy, thereby reducing lipotoxicity and restoring cardiac metabolic balance (Chen et al., 2025). Similarly, Chen and team reported that chicoric acid ameliorated ulcerative colitis in mice by targeting USP9X/IGF2BP2 axis, a novel deubiquitination pathway involved in inflammation and barrier dysfunction (Chen, Shan, et al., 2024). Expanding on target discovery, a state-of-the-art review from Pan and coworkers outlines recent strategies for target identification in natural product research, including proteomics, computational docking and chemoproteomic profiling. These approaches should be critical for optimising bioactivity and reducing off-target effects (Pan et al., 2024). Neuroinflammation, another major frontier, benefits from the anti-inflammatory potential of plant-derived compounds. Zhao and team highlight natural products in microglial modulation, particularly their ability to balance M1/M2 polarisation and reduce neuronal damage (Zhao et al., 2024). The therapeutic potential of SIRT2-mediated deacetylation was also explored in alcoholic liver injury. Based on the work from Wang and colleagues, Carnosol up-regulated SIRT2 level, promoting BAP31 deacetylation at K158, which in turn alleviated endoplasmic reticulum stress and hepatocyte apoptosis (Wang et al., 2025). Lastly, a perspective on pharmacotherapy for liver diseases in China underscores the synergistic integration of Traditional Chinese Medicine (TCM) with modern molecular research. From herbal extracts to EV- and gene-based therapies, this approach exemplifies innovation rooted in heritage (Zhang et al., 2024). Mitochondrial dysfunction and metabolic inflexibility are central to diseases like obesity, NAFLD and heart failure (Ren, Wu, et al., 2021). Targeting these axes offers opportunities to rewire cellular energetics. A comprehensive review from Zhao and associates on drug discovery for cardiovascular metabolic inflammation emphasises the intricate link between metabolic dysregulation and immune activation. Strategies addressing this crosstalk, for example, targeting metabolic checkpoints and inflammatory mediators, should represent the next wave of cardio-therapeutics (Zhao et al., 2025). In inflammatory bowel disease models, FGF1ΔHBS, a low-mitogenic FGF1 variant, protected against DSS-induced colitis by inhibiting MAPK-dependent neutrophil recruitment. This dual anti-inflammatory and barrier-preserving effect reinforces growth factor variants as precision biologics (Feng et al., 2025). A promising group of studies introduces advanced modalities—from cell-based strategies to receptor-targeted signalling—as next-generation interventions. Cell-based therapy in diabetic cardiovascular complications is reviewed by Li and team with attention to stem and progenitor cells. These therapies offer multilineage differentiation and paracrine support, although clinical translation remains challenged by standardisation, delivery and safety concerns (Li et al., 2024). Next, a comparative signalling analysis of Formyl Peptide Receptors (FPR1 and FPR2) from Pajonczyk and team sheds light on their biased agonism and overlapping ligand recognition. While initially thought to mediate distinct inflammatory profiles, their signalling appears more convergent than previously assumed (Pajonczyk et al., 2024). Finally, Bruton's tyrosine kinase (BTK) inhibition emerged as an effective strategy to suppress pathological retinal angiogenesis. Chen and coworkers showed that BTK inhibitors, acting through microglia/macrophage modulation and NLRP3 inflammasome suppression, enhanced anti-vascular endothelial growth factor (VEGF) efficacy without toxicity, offering hope for treatment-resistant ocular diseases (Chen, Liu, et al., 2024). Together, these groups of studies on innovative drug discovery, with emphasis mainly on metabolic and chronic inflammatory diseases, capture a broad yet interconnected landscape of therapeutic innovation. From redefining inflammasome biology to applying omics-guided natural product development, and from mitochondrial repair to immune receptor modulation, the works presented here exemplify the next chapter in precision medicine. Future research will benefit from cross-disciplinary integration—linking immunology, metabolism and regenerative science—to develop safer, more effective treatments for cardiometabolic and inflammatory diseases. Key protein targets and ligands in this article are hyperlinked to corresponding entries in the IUPHAR/BPS Guide to PHARMACOLOGY http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24 (Alexander, Christopoulos, Davenport, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Davies, et al., 2023; Alexander, Fabbro, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Davies, Annett, et al., 2023; Alexander, Fabbro, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Davies, Beuve, et al., 2023; Alexander, Kelly, Mathie, Peters, Veale, Armstrong, Buneman, Faccenda, Harding, Spedding, Cidlowski, et al., 2023; Alexander, Mathie, Peters, Veale, Striessnig, Kelly, Armstrong, Faccenda, Harding, Davies, Aldrich, et al., 2023). Jun Ren and Xin Wang contributed equally to this work. They wrote and revised the manuscript. Xiupin Chen revised the manuscript. No conflict of interest to declare.
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