Miriam Margherita Cortese-Krott

Reflecting the global expansion of research, the British Journal of Pharmacology ( BJP ) has observed a substantial increase in the number of studies focusing on natural products. However, disparities in publication requirements between studies of synthetic small molecules and natural products have led to variable acceptance rates. Building on the progress observed following the 2020 and 2024 BJP editorial on natural products, this updated editorial aims to harmonise expectations across different research domains and promote fair and unbiased assessment of natural product studies. By standardising these criteria, the BJP reaffirms its commitment to maintaining scientific rigour whilst ensuring that the guidelines are clear and practical, thereby contributing to high‐quality research reporting that advances pharmacological science.

In the 2025 novel drug mini‐review, one can take a full measure of the ingenuity that underlies current drug design and development, despite the year's smaller harvest (46 novel drugs) compared to 2024 (53) and 2023 (70). 54% of the novel drugs are first‐in‐class (FIC). The emphasis on proteins/antibodies is maintained (~25% novel drugs in 2025), an industry trend that does not seem to abate. Fewer than half of the novel medicines address major or common disorders. Among the FIC drugs, it is worth mentioning the Na _v 1.8 channel inhibitor suzetrigine, the first non‐opioid approved to palliate acute pain; the first positive allosteric modulator of transient receptor potential melastatin 8 (TRPM8), acoltremon, that increases basal tear production in dry eye disease, a globally common disorder; lerodalcibep, a ‘third generation’ adnectin inhibitor of the protease Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) to treat elevated LDL‐c; and zoliflodacin and gepotidacin, both innovatively targeting bacterial topoisomerases to treat uncomplicated urinary tract infections. Most of the approved medicines target unmet medical need areas and/or orphan indications (the latter alone accounting for 41% of the 2025 novel drugs) by applying imaginative approaches. These approaches include: the combination of two FIC drugs, the RAF/MEK clamp avutometinib paired with the FAK/Pyk2 inhibitor defactinib, to block more efficiently the RAS–RAF–MEK–ERK/FAK oncogenic pathway in low‐grade serous ovarian cancer; fitusiran, the first RNAi therapy for haemophilia, targeting for the first time the production of the natural anticoagulant anti‐thrombin in the liver; and brensocatib, which attenuates the activation of downstream neutrophil proteases by inhibiting the protease DPP1, thereby preventing lung tissue destruction in bronchiectasis. The landscape of novel drugs approved in 2025 reveals that pharmaceutical innovation continues to advance through FIC mechanisms, sophisticated therapeutic approaches, and a strong focus on unmet medical need.

BACKGROUND: Endothelial cells (ECs) are the primary producers of elastin in the internal elastic lamina (IEL) of resistance arteries. These arteries have distinct gaps in their IEL where ECs facilitate heterocellular communication with smooth muscle in a signaling microdomain termed the myoendothelial junction. However, the contribution of the IEL to vasodilation and blood pressure in resistance arteries is not well understood. METHODS: An endothelial-specific elastin knockout mouse (EC-specific Eln ^fl/fl /Cre ⁺ ) was used to alter the IEL and myoendothelial junctions. Myoendothelial junction resident proteins were localized by en face, pressure myography assessed the effect of elastin depletion on vessel dilation, and blood pressure was measured using radiotelemetry. RESULTS: Using single-cell RNA-sequencing, we found Eln mRNA enriched in arterial endothelium. In EC-specific Eln ^fl/fl /Cre ⁺ mice, the localization of the myoendothelial junction resident protein Hbα (α hemoglobin) becomes diffuse and disorganized. Normally, Hbα regulates eNOS (endothelial nitric oxide synthase) by sequestering NO, promoting endothelial-derived hyperpolarization as the predominant vasodilation mechanism. However, in EC-specific Eln ^fl/fl /Cre ⁺ mice, Hbα expression and interaction with eNOS are significantly reduced, corresponding to increased NO signaling via acetylcholine dilation. Intact arteries also exhibit decreased smooth muscle contractility with the diminished IEL. These vascular deficiencies suggested a hypotensive phenotype, but EC-specific Eln ^fl/fl /Cre ⁺ mice’s blood pressure was not different from controls. CONCLUSIONS: Our findings suggest that elastin deficiency in resistance arteries alters their vasoreactive properties, resulting in poor contraction and dilation. Furthermore, the absence of the holes in the IEL mislocalizes Hbα and eNOS in resistance arteries, switching the vasodilatory mechanism from endothelial-derived hyperpolarization to NO signaling, mimicking larger conduit arteries.

Redox signalling governs key physiological and pathological processes, offering diverse therapeutic targets across disease contexts. This editorial introduces a special issue of the British Journal of Pharmacology highlighting recent advances in redox biology, including novel small molecules, non‐canonical nitric oxide and hydrogen sulfide pathways, epigenetic modulation and immune regulation. Together, these contributions illustrate the translational potential of redox‐targeted pharmacology and outline future directions for innovation in the field. LINKED ARTICLES: This article is part of a themed issue Recent Innovations in Targeting Redox Biology for Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.1/issuetoc

BACKGROUND: During obesity, endothelial cells (ECs) become lipid laden, leading to endothelial dysfunction. We tested posttranslational modification on cluster of differentiation 36 (CD36) that may regulate EC lipid accumulation. METHODS: We used an EC-specific Cav1 (caveolin-1) knockout mouse, nitrosation and palmitoylation assays, and whole animal Nγ-nitro-l-arginine methyl ester administration to examine blood lipids. RESULTS: EC-specific Cav1 knockout male mice are hyperlipidemic regardless of diet but retain endothelial cell function. We found these mice have significantly increased NO in response to the lack of Cav1, and the presence or absence of NO toggled inversely EC lipid content and plasma lipid in mice. The NO nitrosated the fatty acid translocase CD36 at the same cysteines that are palmitoylated on CD36. The nitrosation of CD36 prevented its trafficking to the plasma membrane and decreased lipid accumulation. The physiological effect of this mechanism was a reliance on NO for endothelial function and not dilation. CONCLUSIONS: This work suggests that CD36 nitrosation occurs as a protective mechanism to prevent EC lipotoxicity.