Conway et al. integrate phenotypic screening with chemoproteomics to discover an aminoindole that potently clears tau aggregates across multiple tauopathy models via covalently targeting of the ER enzyme P4HB, revealing potential therapeutic strategies for neurodegenerative disease.

Li et al. identify XZA-1 as a small-molecule activator of HADH that increases acetoacetyl-CoA, inducing CBX4 K106 acetoacetylation. This modification suppresses CBX4 SUMO E3 ligase activity, reduces HIF-1α SUMOylation, and attenuates its transcriptional activity.

Theophall et al. identify a therapeutic approach for modifying disease progression in diabetes. They describe an antagonist targeting RAGE, which inhibits the RAGE-DIAPH1 interaction, accelerating wound healing in type 2 diabetic mice and reducing inflammation in peripheral blood mononuclear cell–derived macrophages from patients with type 1 diabetes.

Pequerul et al. map inter- and intratumoral ALDH1 isoform heterogeneity in breast cancer linking ALDH1A3 and ALDH1A2 expression to poor prognosis in high-grade tumors. Integrating profiling, functional assays, and inhibitors, they identify contexts where ALDH1A-selective inhibition may be advantageous, supporting isoform-specific ALDH-targeted strategies.

TNFR2 agonists are attracting translational interest for the treatment of autoimmune diseases. Anany et al. analyzed various TNFR2-targeting nanobody constructs and identified avidity and valence as crucial factors for agonistic activity. The nanobody TNFR2 agonists reached and even surpassed the NF-κB stimulating activity of TNF- and antibody-based agonist benchmarks.

Sainz and Oflaz et al. describe mitochondrial inside-out signaling (mitochondria-initiated signaling mechanisms), provide mechanistic insights into this distinct and underappreciated signaling modality, and discuss how these signaling events influence cellular health with a focus on their implications for neuronal physiology and disease.

Targeting dysregulated inflammasome activity is critical in treating inflammatory disease. Kim et al. identify ZAP-180013 as a selective NLRP3 inhibitor that disrupts inflammasome assembly and overcomes MCC950 resistance. The compound demonstrates efficacy in both local and systemic inflammation models, highlighting its translational therapeutic potential.

Guo et al. discovered that the activation of adenosine 2A receptor relies on allosterically mediated dynamic loss of structural order in the intracellular half of the transmembrane domain. The findings provide important insights into GPCR activation mechanism.

RhoA is a cancer target in colorectal cancer (CRC) but remains undrugged. Koo et al. identified CL16, which covalently targets the unique Cys16 on RhoA subfamily. CL16 binding effectively inhibits RhoA protein, resulting in promising anticancer and anti-metastatic effects. This study highlights RhoA Cys16 as a targetable hotspot for CRC treatment.

He et al. developed a base editor, ACGBEmax, by fusing engineered DNA deaminases and glycosylases, enabling simultaneous substitution of A, C, and G bases. ACGBEmax enables in situ generation of diverse variants, supporting efficient mutagenesis screening in cultured cells and mouse liver.

Bratt, Kilgas et al. describe the SAR-driven design of CAS-010, a selective USP28 probe, alongside a control compound and an inhibitor-resistant mutant. They show that USP28 inhibition mimics p53 pathway loss, reducing p53 transcriptional activity and disrupting 53BP1-USP28 binding, providing mechanistic insight into USP28’s role in p53 signaling.

BLOC-1 and BORC are structurally related complexes that regulate endolysosomal dynamics. De Pace et al. review recent advances in their structure, evolution, and function, highlighting their essential roles in organelle maturation, motility, fusion, tubulation, and biogenesis, and their links to human disease.