Aortic dissection (AD) is a fatal emergency which lacks effective drug therapies. Previous studies demonstrated that histone deacetylase 8 (HDAC8) inhibition provides protective benefits in several cardiovascular diseases, including heart failure, fibrosis, and cardiac hypertrophy. However, the role of HDAC8 in AD remains unclear. In the present study, we investigated the function of PCI-34051, a highly selective inhibitor of HDAC8, in human aortic smooth muscle cell (HASMC) ferroptosis and β-aminopropionitrile (BAPN)-induced AD in mice. The results showed that PCI-34051 and HDAC8 knockdown significantly inhibited cystine deprivation (CD)- and imidazole ketone erastin (IKE)-induced HASMC ferroptosis, as evidenced by an increase in cell viability, reduction in cell injury/death, and lipid peroxidation levels in HASMCs. Transcriptome sequencing analysis revealed that the anti-ferroptosis effect of PCI-34051 was associated with the regulation of activator protein-1 (AP-1). Additionally, co-immunoprecipitation results showed that HDAC8 interacts with c-JUN, a component of AP-1. Overexpression of AP-1 (c-FOS and c-JUN) largely abolished the inhibitory effects of PCI-34051 on HASMC ferroptosis. More importantly, PCI-34051 reduced BAPN-induced AD incidence and aortic rupture mortality in mice by inhibiting HASMC ferroptosis and inflammatory response. Taken together, inhibition of HDAC8 by PCI-34051 may provide a preventive or therapeutic strategy for AD by attenuating HASMC ferroptosis.

Integrated genomic evidence on shared genetic architecture between obesity and psychiatric disorders remains limited. This work utilized multi-level genomic analytic approaches to identify pleiotropic loci, variants, and genes between 14 adiposity traits and 7 psychiatric disorders, including genetic correlation and bidirectional causality as well as gene expression, functional pathway, and druggability, using genome-wide association study data from up to 806,834 individuals of European descent. Based on 67 genetically correlated trait pairs established between the two groups, we identified 17 causal shared genes across 26 tissues, which were enriched in neurodevelopment, neuronal function, cellular transport, and developmental biology. Of these, NEGR1, CTNNB1, TAOK2, and RTN4RL1 were located in the druggable genome, and CTNNB1 and NT5C2 were clinically actionable. Mendelian randomization further supported extensive bidirectional causal associations. These findings provide robust evidence for a shared genetic etiology between adiposity and psychiatric disorders, underscoring mechanistic links and prioritizing actionable targets for comorbidity intervention.

Tau is a microtubule-associated protein traditionally involved in a collective group of disorders termed “tauopathy”, including Alzheimer’s disease. Tau protein self-aggregates and forms neurofibrillary tangles in neurons, which are considered a pathological hallmark of tauopathies. While the roles of neuronal tau in tauopathies have been extensively investigated, recent studies have shed light on its roles in other diseases without tau pathology and in other cells. In this review, we aim to discuss the “atypical” pathological involvement of tau in diseases other than tauopathies, including brain diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury), vascular diseases (stroke and hypertension), diabetes, and cancers. We have discussed the expression and functions of tau in cell types other than neurons, and have summarized the evidence supporting a role of tau in these diseases. These cross-disease studies collectively suggest that tau protein is more broadly implicated in mechanisms such as axonal instability, dysregulated cell signaling, inflammatory activation, and cell death, independent of its aggregation, contributing to our knowledge of the functions of tau and the myriad ways in which it may be involved in pathological processes.

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations, found in 25%–30% of acute myeloid leukemia (AML) patients, cause poor prognosis and resistance to FLT3 tyrosine kinase inhibitors (TKIs). We show that APG-115 selectively kills FLT3-ITD cells by activating p53. This critically upregulates TRIM22 (Tripartite motif-containing protein 22), an essential E3 ubiquitin ligase that directly binds FLT3-ITD, promotes its polyubiquitination, and induces its proteasomal degradation. This TRIM22-mediated mechanism offers a novel strategy to overcome intrinsic and acquired TKI resistance. Unlike inhibitors such as AC220, which suppress FLT3 signaling but downregulate p53, APG-115 restores p53 function and induces TRIM22, enabling potent synergy with FLT3 inhibitors. TRIM22 is essential for APG-115’s suppression of leukemia stem cells, inducing cell cycle arrest, myeloid differentiation, and reduced clonogenic potential. The combination of APG-115 and AC220 significantly enhances apoptosis in FLT3-ITD AML models and primary cells, while sparing normal cells. It shows robust efficacy in preclinical xenograft models, reducing tumor burden and extending survival. This work establishes targeting the p53/TRIM22 axis, reliant on TRIM22’s unique activity against FLT3-ITD, as a highly promising therapeutic approach for FLT3-ITD AML, including resistant disease.

A growing body of evidence suggests that aging is not simply the accumulation of damage, but a systemic progression of increasing entropy across biological scales. Synthesizing concepts from thermodynamics and information theory, we outline a tentative three-stage entropy model of the lifespan: order-building development, homeostatic adulthood, and disorder-dominant aging. Within this model, we attempt to reframe the established hallmarks of aging as interconnected nodes in an entropy-centered network and detail the multiscale manifestations of disorder from molecules to systems. To quantify this trajectory, we introduce a Multiscale Entropic Aging Index (MEAI) as a proof-of-concept conceptual framework, designed to integrate measurements of disorder across biological levels. This framework seeks to offer a potential unifying, quantitative language for aging research and suggests that entropy reduction could serve as a testable mechanism underlying interventions, laying a principled foundation for the future development of biomarkers and rejuvenative strategies.