Nature Metabolism, Published online: 06 October 2026; doi:10.1038/s42255-026-01638-1The NLRP3 inflammasome has crucial roles in immunity and disease and is a key target for therapeutic efforts. In this issue of Nature Metabolism, Liu et al. show that l-arginine can inhibit inflammasome activation, highlighting the potential of dietary arginine supplementation as a treatment for NLRP3-related disease.

TRAM is a regulator of myddosome assembly through dissociating MyD88 from the TLR–TIRAP complex to enable myddosome maturation and durable downstream signal transduction.

The NLRP3 inflammasome drives chronic inflammatory diseases from asthma to gout, yet most small-molecule inhibitors target the NLRP3 protein directly and carry adverse-effect profiles that limit their...

The membrane-active peptide Pep19-2.5 reduces harmful inflammation by blocking activation of the NLRP3 inflammasome at trans-Golgi network membranes. By targeting key membrane interactions, Pep19-2.5...

A previously entirely unknown mode of TLR signal transduction is elucidated.

Nature Reviews Immunology - Ruslan Medzhitov shares his thoughts on the balance between generating data and developing theories in immunology, with a focus on exploring the rules that govern...

The NLRP3 inflammasome is a validated therapeutic target in inflammatory, metabolic, and neurodegenerative diseases. Epigenetic regulators, particularly histone deacetylases (HDACs), have emerged as key modulators of inflammasome priming and activation. Recent advances in medicinal chemistry have provided new chemical modalities for the mechanistic interrogation and the potential therapeutic modulation of NLRP3 signaling. This Perspective dissects the mechanistic interface between HDAC-dependent epigenetic control and NLRP3 signaling and highlights emerging chemical tools, including isoform-selective inhibitors and targeted protein degraders. We discuss the challenges of isoform selectivity, species-specific differences, and the therapeutic potential of HDAC-based strategies to attenuate aberrant NLRP3 activity while minimizing off-target effects. Understanding this epigenetic-inflammasome crosstalk may provide a framework for translating epigenetic modulation into innovative treatments for inflammasome-driven diseases.

Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain–containing 3 (NLRP3) inflammasome hyperactivation and e...

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NLRP3 inflammasome activation is critical for the induction of protective immunity, but molecular insights are still lacking. Here, the authors express NLRP3 variants targeted to different cellular lo...

imageimageContrary to the prevailing model, ligand-induced TLR4 endocytosis is not a prerequisite for endosomal TLR4 signaling in macrophages. TLR4 endocytosis requires the TIR domain, PLCγ2, SYK and ...

Nature - Proteasomal degradation of cellular proteins generate defence peptides constitutively and in response to bacterial infection. Such peptides might provide a source of natural antibiotics...

Background The endogenous nucleotide adenosine 5′-tetraphosphate (Ap4) is a potent vasoconstrictor. Despite its structural similarity to the danger signal adenosine 5’-triphosphate (ATP), the immunomo...

Toll-like receptor 8 (TLR8) recognizes viral and bacterial RNA, initiating inflammatory responses that are crucial for innate immunity. Dysregulated TLR8 signaling contributes to autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, driving chronic inflammation and tissue damage. Therefore, targeting TLR8 has gained attention as a promising therapeutic strategy. We report a novel selective TLR8 antagonist scaffold identified through computational modeling and simulation. In silico-guided rational drug design and synthesis led to potent isoxazole-based compounds that were characterized by structure–activity relationships. The most active compounds inhibited TLR8-mediated signaling in cell lines and primary cells, reduced MyD88 recruitment, suppressed NF-κB- and IRF-dependent signaling, and decreased inflammatory responses. In silico and pharmacological analyses demonstrated competitive binding to the pocket of chemical ligands within the TLR8 dimerization interface. These highly selective and potent TLR8 antagonists possess favorable physicochemical properties, representing potential clinical candidates for TLR8-targeted therapy.

Mapping the metabolic effects of drugs helps define their mode of action.

This study explores PROTACs for NLRP3, the key player in innate immunity. We utilized a thiophene analogue of the NLRP3 inhibitor MCC950 and employed CuAAC chemistry for the assembly of PROTACs bearin...

Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors. Here, we investigated the effects of the synthetic LPS-neutralizing peptide Pep19–2.5 on human P2X receptors in cells of the innate immune system. Pep19–2.5 concentration-dependently triggered Ca2+ influx, interleukin (IL)-1β, and lactate dehydrogenase (LDH) release in Toll-like receptor-stimulated human macrophages and monocytes. Ca2+ influx was mediated at least partially by P2X7 receptors, and IL-1β and LDH release by P2X7 receptors, respectively. Confocal microscopy confirmed the colocalization of Pep19–2.5 with P2X7 receptors. Pep19–2.5-induced IL-1β release in primed cells was dependent on K+ efflux, caspase-1, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasome. In the presence of the P2X7 receptor agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate, Pep19–2.5 reduced IL-1β and LDH release. In 1321N1, astrocytoma cells stably transfected with human P2X receptors, Pep19–2.5 potently modulated P2X7 and P2X4 receptors (IC50 values of 0.346 and 0.146 μM, respectively) but showed less (P2X1, P2X3) or no activity (P2X2) at other P2X receptor subtypes. Our findings underline the potential of LPS-neutralizing peptides as modulators of P2X receptors, thus expanding their applicability beyond the treatment of sepsis to the treatment of inflammatory diseases.

Broad discussion is needed to chart a path forward.

A loss-of-function genetic screen identifies the ER-resident protein CCDC134 as an essential regulator of Toll-like receptor (TLR) responses. CCDC134 binds

SurfDock is a method for predicting protein–ligand complex structures by leveraging multimodal protein information and generative diffusion frameworks. Its results can be generalized to unseen protein...

Alzheimer’s disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex ...

The Graduate Research Training Group 2873 “Tools and Drugs of the Future – Innovative Methods and New Modalities in Medicinal Chemistry”, funded by the German Research Foundation (DFG) offers 12 PhD P...

Mitochondria control metabolism, cell death, and innate immunity, yet their reciprocal mechanistic connections are elusive, as is the conserved physiological function of the NLRP3 inflammasome. Saller...

Toll-like receptors are key mediators of immune responses, but gaps remain in understanding their signalling. Here, the authors introduce an optical biosensor assay to detect real-time TLR activation ...