Artificial intelligence has rapidly advanced molecular science, yet progress has largely unfolded through specialized models tailored to specific tasks. In this issue of Cell, Peng et al. introduce PocketXMol, a unified 3D generative framework that reframes molecular design problems as conditional reconstruction of atomic interactions. Demonstrations across design scenarios highlight its potential in molecular engineering.

New approach methodologies that are human-centered, such as stem cells, organoids, and in silico models, can span the full drug discovery pipeline—from disease modeling to efficacy testing—and hold promise as both tools for drug discovery and potential therapies.

The E3-ome defines the human repertoire of ubiquitin E3 ligases, creating a unified resource that maps their diversity across the ubiquitin and ubiquitin-like systems. By consolidating fragmented knowledge, this framework provides a foundation for studying ubiquitin signaling and accelerating discovery.

(Cell 188, 1984–2002.e1–e6; April 3, 2025)

Although bowhead whales remained genetically stable through 11,000 years of Holocene environmental change, commercial whaling upended this long-term stability, driving population subdivision and genomic erosion that are still unfolding today.

(Cell 188, 6283–6300.e1–e10; October 30, 2025)

A multi-omic single-cell atlas of the aging mouse brain reveals cell-type-specific transposon methylation changes, strengthening of 3D genome boundaries, and regionally heterogeneous aging signatures. These findings offer a resource to understand the molecular mechanisms of brain aging and guide future research on neurodegeneration.

Li et al. developed a ferritin aggregation cell engager that helps CAR T cells better recognize and attack leukemia cells without re-engineering the CAR itself. This versatile platform overcomes antigen modulation and enables combination with chemotherapy.

Xiao et al. identify α-KG as a rosacea-associated metabolite that activates the OXGR1-Gq-MYL9 axis in the vascular smooth muscle cells to boost contractility and suppress pathological vasodilation underlying erythema. Cryo-EM reveals a bipartite-acid pocket of OXGR1 that enables structure-guided development of A-1, a selective agonist that alleviates erythema in rosacea-like models.

SPYTAC is a synthetic peptide-programmed targeted protein degradation platform harnessing LRP1 to drive lysosomal degradation of extracellular amyloid-β in the brain and periphery. In 5×FAD mice, SPYTAC treatment efficiently degrades amyloid-β, preserves neurons, and improves cognition with reduced neuroinflammation and microhemorrhage when compared with antibody therapy.

Enhancing circadian amplitude in mouse hypothalamic paraventricular nucleus neurons by 3′-deoxyadenosine treatment alleviates age-related pathologies and extends lifespan.

The development of genetically encoded fluorescent reporters, along with their corresponding knock-in mouse lines for labeling α-Syn inclusions, enables diverse applications in studying the propagation and pathological effects of α-Syn inclusions in the live brain.

Yibo et al. identify protein pyruvylation as a post-translational modification that can modulate immune signaling and host antiviral response.

Nuclear speckles are key subnuclear structures that regulate gene expression in GC-rich regions. This work shows that the evolution and expansion of core speckle proteins were crucial for the increased GC content seen in amniote genomes.

MicrobeAtlas (www.microbeatlas.org) is an integrated, reference-based resource for truly planet-wide microbiomics, analyzing hundreds of thousands of microbial lineages across diverse environments, conditions, and technologies.

Deep proteome profiling of over 5,000 cerebrospinal fluid samples by mass spectrometry maps protein alterations across major neurological disorders, resolving key sources of variation as well as shared and disease-specific signatures. This framework yields a 22-protein assay that improves the differential diagnosis of multiple sclerosis from other inflammatory conditions, particularly in diagnostically challenging oligoclonal band-negative individuals.

Precise genome editing of the rice strigolactone receptor DWARF14 confers robust, transgene-free antiviral resistance by blocking viral suppression of endogenous RNA silencing, offering a promising strategy for durable disease protection without a yield penalty.

An in vivo, noncanonical ferroptosis pathway, critical for tumor supression, is driven by reactive oxygen species-induced phosphatidic acid peroxidation at the ER under the control of the GPX1-OSBPL8 signaling axis.

A versatile, atom-level generative AI model enables unified pocket-interacting tasks, from docking to de novo design, and demonstrates robust experimental validation for both small-molecule and peptide therapeutics.

A planetary-scale analysis of over 85,000 metagenomes establishes a framework for exploring the structure and drivers of global microbial habitats, revealing that generalist species bridge ecological boundaries to mediate gene flow across disparate habitats, including the dissemination of antimicrobial resistance.