Lingyun Dai

Aging is a well-recognized risk factor in cardiovascular diseases (CVDs), primarily due to its association with the gradual decline in cardiac function. This decline significantly influences the pathogenesis of common CVDs such as myocardial infarction and heart failure. Despite the existence of several proteomic atlases of the heart, the spatially resolved proteomic dynamics essential for understanding region-specific aging mechanisms in cardiac tissue remain incompletely characterized. In this study, we conducted a region-resolved quantitative proteomic profiling for various murine cardiac regions at three distinct stages of aging (3, 12, and 20-month-old), quantifying 6 650 proteins in the heart. Leveraging integrated bioinformatics and machine learning frameworks, we uncovered that FTL1 and SERPINA3K exhibit strong age-associated expression changes across all cardiac regions. Mechanistically, the knockdown of Ftl1 led to cardiomyocyte ferroptosis and senescence, phenotypes that were ameliorated by the ferroptosis inhibitor Ferrostatin-1. Furthermore, the depletion of Serpina3k exacerbated senescence and collagen deposition through the activation of the cGAS-STING-PERK axis, effects that can be reversed via the overexpression of Serpina3k or the knockdown of Sting . The protective effect of SERPINA3K was also demonstrated in vivo through AAV9-mediated cardiomyocyte-specific overexpression in middle-aged mice, which attenuated the cGAS-STING-PERK axis and mitigated age-related fibrosis. These results strongly demonstrated that FTL1 and SERPINA3K function as key regulators of cardiac aging. Collectively, this study provides a valuable region-resolved proteomic atlas of cardiac aging and identifies key protein regulators, thereby uncovering potential targets for cardio-protective interventions against age-related cardiovascular disorders.

Iron (Fe) and copper (Cu) are vital micronutrients that regulate many critical physiological processes in the human body, with their homeostasis in the central nervous system (CNS) being essential for proper neuronal function. Disruptions in their metabolism and regulatory pathways have been associated with the pathogenesis of various forms of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite growing research on metal homeostasis, the intricate molecular mechanisms that link iron and copper metabolism to the initiation and progression of NDDs remain insufficiently elucidated. In this review, we provide a systematic overview of the metabolic processes of iron and copper in the body and CNS, highlighting their interactions with many metal‐binding proteins, including transporters, storage proteins, and important intrinsically disordered proteins (e.g., amyloid β‐protein, tau, and alpha‐synuclein) involved in NDDs. We further dissect the downstream effects of metal ion dyshomeostasis on cellular redox balance, neuroinflammation, autophagy, organelle interaction network, and cell death. Additionally, we discuss current therapeutic strategies aimed at targeting iron and copper dyshomeostasis, as well as the emerging role of artificial intelligence in this field of research. By integrating metal metabolism, metal–protein interactions, the effect of metal dyshomeostasis on downstream biological processes, and potential intervention strategies, this review serves as a comprehensive reference for understanding the pathogenesis of NDDs and offers new perspectives for developing effective therapeutics. Overall, this review underscores the significance of reinstating metal balance for the treatment of neurodegeneration.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a clinicopathological syndrome characterized by abnormal accumulation of fat within hepatocytes, and there is currently no standardized clinical treatment available. Consequently, there is an urgent need to discover new pharmacological interventions and to investigate novel therapeutic targets for MASLD. Melatonin, known for its multifaceted biological functions, has shown therapeutic potential for the treatment of MASLD. However, the underlying mechanisms remain unclear, particularly since the direct targets of melatonin remain poorly understood. In our study, we found that melatonin significantly improved various indicators in a mouse MASLD model and protected palmitic acid-induced mouse hepatocytes from lipid accumulation. We successfully identified and validated the mitochondrial trifunctional enzyme α-subunit HADHA as a binding target for melatonin using the cellular thermal shift assay (CETSA). This interaction enhanced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which subsequently promotes mitochondrial biogenesis and accelerates lipid metabolism. In addition, melatonin reduced lipid accumulation and ameliorated MASLD through its regulatory effect on key proteins involved in fatty acid metabolism, including acyl coenzyme A oxidase 1 (ACOX1), cluster of differentiation 36 (CD36), and fatty acid synthase (FASN). Importantly, these beneficial effects were diminished when HADHA was knocked down. In conclusion, our study suggests that melatonin ameliorates MASLD through HADHA-mediated regulation of mitochondrial biogenesis and lipid oxidation, highlighting its potential as a promising therapeutic agent for MASLD. These results offer novel insights into the role of melatonin in the treatment of MASLD.

Supplementary figure S6. Senescent features are diminished in established lung metastasis derived from CTTN KD-induced senescent CTCs

Supplementary figure S17. The MEK inhibitor, cobimetinib, sensitizes senescent CTCs to apoptosis

Supplementary figure S7. Transcriptomic and proteomic changes of melanoma cells upon cortactin depletion

Supplementary figure S3. Single-cell RNA-seq of early CTC cultures reveals heterogenous expression of CTTN in single CTCs that are inversely correlated with the senescence state