Innate immunity provides a critical first line of defense against pathogens and homeostatic perturbations. Pattern recognition receptors detect these disruptions and initiate immune responses through multi-protein complex formation to drive inflammatory signaling and cell death pathways. Key cytosolic complexes formed by these sensors include inflammasomes and PANoptosomes. Inflammasomes induce caspase-1 activation and the subsequent maturation of interleukin (IL)-1β and IL-18, and they can act as integral components of larger PANoptosomes, whose formation and functions have been defined by genetic, biochemical, and single-cell imaging evidence. PANoptosomes induce lytic, inflammatory cell death (PANoptosis) and promote the release of damage-associated molecular patterns (DAMPs) and cytokines beyond IL-1β and IL-18, including TNF, IFNs, IL-6, and others. Given their critical functions in driving cell death and the release of cytokines and DAMPs, dysregulation of innate immune sensors is associated with a wide range of diseases, including infections, autoinflammatory syndromes, cardiovascular disorders, neurodegeneration, metabolic conditions, and cancer. Therefore, understanding innate immune sensors and how they assemble inflammasomes and PANoptosomes to drive cell death is critical for identifying therapeutic strategies. In this review, we discuss innate immune sensors that form inflammasomes and PANoptosomes, such as NLRP1, NLRP3, NLRC4, AIM2, Pyrin, and others. We highlight recent structural and mechanistic insights into these sensors, along with emerging structural studies of inflammasome assemblies and the biochemical and functional evidence supporting the formation of PANoptosomes. Given the physiological relevance of innate immune sensors and the complexes they form across the disease spectrum, an improved understanding of their structure-function relationships will be critical for informing therapeutic strategies that target these molecules, their associated complexes, and their physiological functions.

Natural killer (NK) cells are central to antitumor immunity but rapidly lose function in the tumor microenvironment (TME). Here, we identify CD55, previously recognized as a complement regulatory protein, as an inducible membrane organizer that coordinates activating receptor signaling to potentiate NK cell-mediated antitumor responses. Upon initial tumor encounter, NK cells upregulate CD55 via an NKG2D-p65 transcriptional axis. Unlike in T-cells, where it has a known co-stimulatory role, CD55 on NK cells directly engages tumor-expressed CD97 in trans to trigger lipid raft aggregation and LCK activation, acting as a self-sufficient primary signal initiator that drives cytotoxicity. However, upon prolonged tumor exposure, CD55 expression on NK cells progressively declines, coinciding with the well‑recognized downregulation of NKG2D upon chronic exposure. Within the TME, this loss of CD55 causally impairs NK-cell function. In cancer patients, low CD55 expression in tumor-infiltrating NK cells correlates with poor clinical outcomes. Restoring CD55 expression in both conventional and chimeric antigen receptor-engineered NK cells augments LCK signaling, enhances effector function and persistence, and improves antitumor efficacy in vivo. Thus, NK cells deploy a CD55-dependent autonomous activation mechanism upon tumor encounter, whereas chronic exposure drives CD55 loss and functional dysfunction, a state that can be therapeutically reversed by CD55 restoration.

In gymnosperms such as Ginkgo biloba, the regulatory role of large introns remains unclear. To address this, we conducted integrative multi-omics analyses of chromatin accessibility, three-dimensional chromosomal architecture, histone modifications, DNA methylation, RNA polymerase II occupancy, and gene expression in Ginkgo, complemented by laboratory experiments. We first identified a plant-specific factor, plant-Loop Factor (p-LoopF), which shares ~40% sequence similarity with human CCCTC-binding factor (CTCF). p-LoopF binds specifically to the consensus motif recognized by human CTCF and is significantly associated with chromatin looping, but it lacks canonical CTCF functional features, including motif orientation dependence, chromatin insulation activity, and statistically significant correlations with cohesin subunits. Through integrative multi-omics analyses, we propose a regulatory hypothesis in which p-LoopF-associated chromatin loops are correlated with the recruitment of distal enhancer-like regulatory regions, with large introns serving as a key regulatory context for these interactions. p-LoopF also localizes to promoters and distal intergenic regions, correlating with transcriptional regulation and local chromatin organization. We characterized large introns as regions enriched for chromatin loops, p-LoopF binding sites, and enhancer-like elements, which are strongly associated with the transcriptional regulation of their host genes. Additionally, active histone marks and DNA demethylation were enriched near the boundaries of large introns, particularly around splice sites, suggesting that splicing regulation differs between large and small introns.

Vein occlusion (VO), including deep venous thrombosis (DVT) and retinal vein occlusion (RVO), is a common cause of multiple diseases that severely compromise the quality of life of affected individuals. Epidemiological evidence indicates that VO prevalence increases in cold seasons, yet the underlying mechanism remains unknown. Here, we show that cold exposure markedly elevates peripheral platelet counts, thereby aggravating VO in mouse models. Cold-augmented thrombocytopoiesis depends on the activation of adipose thermogenesis and subsequent increase in circulating free fatty acid (FFA) levels. Mechanistically, FFA-β-oxidation promotes acetyl-CoA production, which upregulates and stabilizes C/EBPα by shifting the balance between p300 acetyltransferase and SIRT1 deacetylase. Acetyl-C/EBPα transcriptionally upregulates GATA-1 and NF-E2 for megakaryocyte maturation and platelet production. Depletion of adipose triglyceride lipase PNPLA2, megakaryocyte-specific knockout of key β-oxidation enzyme CPT1α, or pharmacological inhibition of CPT1α and p300 abolishes cold-augmented thrombocytopoiesis and alleviates DVT and RVO in mouse models. In healthy volunteers, tolerable cold exposure activates adipose thermogenesis, increases circulating FFA levels, and increases platelet counts. Moreover, a retrospective cohort study of 425 patients reveals elevated platelet counts and higher DVT incidence during cold seasons. Similarly, increased platelet counts are observed in 448 patients with RVO at the time of diagnosis in cold seasons. Our study provides novel mechanistic insights into the increased VO risk induced by cold exposure and proposes a new therapeutic paradigm for VO by targeting megakaryocyte metabolism.

Ferroptosis has long been regarded as a cell-autonomous form of regulated cell death driven by iron-dependent lipid peroxidation. Recent work, however, suggests that ferroptotic commitment can extend beyond the initiating cell, spreading to neighboring cells and, in some contexts, across tissue-scale distances. Multiple, non-mutually exclusive modes of contagion have now been described, including reactive oxygen species-triggered death waves, direct membrane contact-dependent transfer, and extracellular vesicle-mediated paracrine signaling. These findings redefine ferroptosis from a single-cell execution pathway into a spatially coordinated, multicellular process. In this perspective, we integrate mechanistic insights with experimental evidence on ferroptotic contagion and propose a unifying, multiscale framework in which distinct modes of transmission operate over different spatial scales, from short-range membrane transfer to longer-range oxidative and extracellular relay mechanisms. We discuss how nonlinear redox amplification, membrane biophysics, and tissue architecture together determine the dynamics, limits, and patterning of ferroptotic injury in vivo. This emerging framework has important implications for developmental tissue remodeling, the progression of organ injury, and ferroptosis-based cancer therapy. More broadly, defining how ferroptotic contagion is initiated, constrained, and manipulated therapeutically may help establish ferroptosis as a fundamental organizing principle for understanding tissue-level regulation and pathological escalation.

During primordial germ cell (PGC) specification, repression of somatic programs is essential for the establishment of germline identity. However, mechanisms that safeguard PGC fate thereafter remain unknown. Here, we identify the E3 ubiquitin ligase TRIM37 as a critical safeguard of PGC fate during migration. Trim37 deficiency causes severe PGC defects beginning at embryonic day 9.5 (E9.5) with complete PGC depletion by E12.5, and leads to an aberrant transition toward somatic cell states. Mechanistically, TRIM37 binds TRIM28 through its MATH domain and ubiquitinates TRIM28 via its RING domain, enhancing the TRIM37-TRIM28 interaction and promoting the nuclear retention of TRIM37. Forced nuclear export of TRIM37 results in PGC loss. Moreover, disruption of TRIM37 ligase activity or mutation of TRIM28 ubiquitination sites compromises PGC maintenance. We further show that the TRIM37-TRIM28 complex, likely acting in cooperation with AP2γ, restricts chromatin accessibility and H3K27ac levels at somatic gene loci, thereby repressing somatic transcriptional programs in PGCs. Together, our findings uncover a TRIM37-TRIM28-AP2γ regulatory complex that safeguards germ cell fate by preventing the activation of somatic transcriptional programs during PGC migration.

The derivation of authentic embryonic stem cells (ESCs) across mammalian species remains a major challenge. Here, we report the development of a defined, serum-free culture system, termed 6iL/E4, that enables the derivation and long-term self-renewal of ESCs across diverse mammalian species. Through systematic dissection of signaling pathways, we identified conserved regulatory modules involving GSK3α, WNT, STAT3, PDGFR, and MEK/ERK signaling. The optimized 6iL/E4 conditions support stable derivation and expansion of ESCs from mouse, rat, rabbit, and bovine embryos. For rabbit, ESC derivation required supplementation with the LATS inhibitor TDI-011536 (TDI), and 6iL/TDI-cultured rabbit ESCs exhibited chimera-forming capability. In bovine ESCs, inducible expression of Klf2 and Nanog reinforced pluripotency and promoted in vivo chimeric contribution. Importantly, we demonstrated that 6iL robustly establishes and maintains human pluripotent stem cells in a naïve-like state. These findings reveal conserved principles underlying ESC self-renewal across divergent mammalian species and provide a universal platform for cross-species stem cell research, disease modeling, and biotechnological applications.