S-palmitoylation, a reversible post-translational modification, regulates critical biological processes and represents a promising therapeutic target for diverse human diseases. Over the past decade, human α/β hydrolase domain (ABHD) proteins have emerged as key regulators of the dynamic S-palmitoylation/depalmitoylation cycle, yet a systematic overview of their roles in this modification remains lacking. This review provides a comprehensive summary of the functions of emerging ABHD proteins-including ABHD17A/B/C, ABHD16A, ABHD10, ABHD7, and ABHD8-in the dynamics of S-palmitoylation and depalmitoylation cycle, along with their molecular mechanisms, structural features, and substrate specificities. Associations between dysregulated ABHD protein-mediated S-palmitoylation and various diseases, including cancers, neurological disorders, degenerative diseases, viral infectious diseases, metabolic diseases, and reproductive disorders are discussed. Predictive criteria for uncharacterized ABHD proteins and prospective targeted therapeutic strategies are also proposed. This review provides mechanistic insights into emerging ABHD proteins in S-palmitoylation/depalmitoylation, and lays a foundation for developing novel diagnostic markers and precision therapies for S-palmitoylation-related diseases.

The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood-brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.

Recent studies indicate the gut microbiome as a crucial regulator of cancer therapy, yet its role in urological malignancies remains incompletely understood. High rates of resistance to cornerstone treatments, including immune checkpoint inhibitors (ICIs) and intravesical immunotherapy, represent major clinical hurdles. Synthesizing emerging evidence on the gut-tumor axis shows how the gut, urobiome, and intratumoral microbiota (IM) collectively influence the tumor microenvironment (TME) and therapeutic outcomes. This influence extends beyond chronic inflammation and direct genotoxicity to include metabolic crosstalk that shapes the host immune landscape. The composition of the gut microbiota is emerging as a potential predictive marker for ICI efficacy, as the enrichment of certain beneficial taxa has been linked to favorable outcomes. Microbial metabolic pathways are also implicated in therapeutic resistance; microbial metabolism of host hormonal precursors is hypothesized as one mechanism contributing to resistance to endocrine therapies. Furthermore, systemic and local communities may interact, wherein gut-derived metabolites can enhance systemic immunotherapy, while the local urobiome may interfere with intravesical treatment efficacy. However, clinical translation faces major impediments. A primary challenge is the lack of methodological standardization, which generates observational inconsistencies and complicates causal inference. Future progress will therefore depend on large-scale, longitudinal, multiomics clinical trials using harmonized protocols. This review provides a comparative narrative synthesis of shared and distinct mechanisms across the three major urological cancers and outlines priorities for future interventions and precision medicine in urologic oncology.

Lipotoxicity-induced endothelial dysfunction impairs wound healing in obesity and type 2 diabetes, yet the underlying mechanisms remain elusive. While Angiogenin promotes endothelial function, its role under lipotoxic stress has been unknown. Here, we demonstrate for the first time that Angiogenin effectively protects against lipotoxicity-induced delayed skin repair. In a cellular lipotoxicity model induced by oleic and palmitic acids (OPA) using human umbilical vein endothelial cells (HUVECs), the levels of Angiogenin decreased in a time- and dose-dependent manner. Meanwhile, a similar reduction was also observed in the skin tissue of high-fat diet/streptozotocin (STZ)-induced diabetic mice and Apolipoprotein E (APOE)[-/-] mice. Restoring Angiogenin levels significantly enhanced endothelial proliferation, migration, and angiogenesis, rescuing OPA-induced impairment. Through RNA-seq and subsequent validations, we provide novel mechanistic insight into Angiogenin's protective action: Angiogenin directly binds and stabilizes Caveolin-1 (Cav1) mRNA, leading to increased Cav1 expression. Critically, we show that the Angiogenin-mediated endothelial rescue is strictly dependent on this Cav1 upregulation. Furthermore, topical administration of Angiogenin peptide significantly accelerated wound closure and neovascularization in both APOE[-/-] and high-fat diet/STZ-induced diabetic mice. Collectively, our study unveils a novel Angiogenin-Cav1 axis in endothelial protection, positioning Angiogenin as a promising therapeutic candidate for lipotoxicity-induced impairment of skin wound healing.

Swine leukocyte antigen class I (SLA-I) molecules are swine orthologs of human MHC class I molecules and are encoded by three classical loci, SLA-1, SLA-2, and SLA-3. By engaging T-cell receptors (TCRs), these cell-surface proteins present antigenic peptides, whose binding specificity is largely dictated by the architecture of the peptide-binding groove (PBG) and its constituent pockets. Although early SLA-I research primarily emphasized molecular and functional features, recent advances in structural biology have yielded an increasing number of crystal structures of SLA-I-peptide complexes, providing critical insights into the principles of peptide presentation and T-cell recognition in pigs. In this review, we examine the structural features of SLA-I molecules, focusing on the PBG and binding pockets that accommodate peptide anchor residues. Structural studies revealed that the SLA-I PBG, while architecturally conserved, exhibits pronounced allelic polymorphism and plasticity, predominantly within its six binding pockets (A-F). A key insight is the profound functional impact of micropolymorphisms; for instance, single-residue variations in pockets such as D can dramatically alter the peptide-binding specificity and repertoire. Finally, we highlight current knowledge gaps and future research directions to facilitate the exploitation of SLA-I structural features for targeted vaccine design and immunotherapeutic development, thus addressing the challenges of porcine immune recognition.