Hou-Zao Chen

BACKGROUND: Pathological cardiac remodeling is a hallmark of numerous cardiovascular diseases and develops into heart failure. As a systemic disease, effective treatments for cardiac remodeling from a tissue crosstalk perspective are still significantly unmet. METHODS: Hepatocyte-specific ChREBP (carbohydrate response element binding protein) knockout (KO) or overexpressed mice, global ApoM (apolipoprotein M) KO and adeno-associated virus-mediated hepatic ApoM knockdown or overexpressed mice, cardiomyocyte-specific ChREBP overexpressed mice, as well as S1PR1 (sphingosine-1-phosphate receptor 1) knockdown mice were used in isoproterenol- or transverse aortic constriction-induced cardiac remodeling models. RNA sequencing and liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis were used to detect changed pathways and the interaction between ChREBP and SURF4 (surfeit 4). RESULTS: We found increased ChREBP expression in the liver, but not in the heart, especially in the cytosol of hepatocytes, but not the nucleus, in isoproterenol- or transverse aortic constriction-induced mice. Hepatocyte-specific ChREBP deficiency protected against isoproterenol or transverse aortic constriction-induced cardiac remodeling. Mechanistically, hepatocyte ChREBP deficiency increased ApoM expression in the liver and its secretion, not by transcriptional regulation of ApoM, but by increasing its secretion through the release of SURF4. ApoM overexpression in the liver or ApoM-containing high-density lipoprotein (HDL) injection can both ameliorate cardiac remodeling through the S1P (sphingosine-1-phosphate)/S1PR1 pathway in the heart. CONCLUSIONS: This work identifies the hepatic ChREBP-SURF4-ApoM axis as a critical pathway in cardiac remodeling, and induction of hepatic ApoM secretion constitutes a new promising approach for treating cardiac remodeling and heart failure.

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare and severe encephalopathy linked to neurodevelopmental disorders, yet the connection between metabolic dysfunction and impaired neurogenesis remains unclear. In this study, we demonstrate that the loss of Echs1 in neural stem/progenitor cells (NSPCs) leads to fatty acid accumulation, which hinders proliferation and differentiation while promoting apoptosis. Mechanistically, Echs1 deficiency increases crotonyl-CoA levels, resulting in global histone crotonylation (Kcr) with an enrichment of H3K9cr. Neurodevelopmental gene promoters, such as the endoplasmic reticulum (ER) stress regulator Atf4, acquire H3K9cr. Atf4 then upregulates fatty acid synthase (Fasn), creating a feed-forward loop that exacerbates lipid accumulation. Inhibiting Fasn can rescue these defects. Alleviating ER stress through tauroursodeoxycholic acid (TUDCA) or Atf4 inhibition restores neurogenesis in vitro and enhances survival in vivo. This study uncovers an Echs1-H3K9cr-Atf4-Fasn axis that links metabolism to neurogenesis through epigenetic reprogramming and suggests TUDCA as a potential treatment for ECHS1D.

Human heart development requires coordinated gene regulation across spatially organized tissues. However, the principles by which the heart establishes spatially organized structures and how regional programs integrate to orchestrate coordinated development remain unclear. Here, we generate a spatiotemporal transcriptomic atlas of the developing human hearts, profiling 30 sections spanning 8-15 post-conception weeks. By treating each spatial spot as a multicellular unit, we resolve anatomically coherent compartments and identify specialized subpopulations, including the Papillary muscle and Atrioventricular Plane. Focusing on the ventricle, trajectory inference reveals a continuous endocardium-to-epicardium transcriptional gradient, accompanied by coordinated changes in gene expression, transcription factor activity, and signaling pathways. Integrative developmental analysis identifies shared maturation-associated transcriptional changes, with increasing contractile and metabolic programs and declining proliferative signatures, alongside region-specific specialization across spatial domains. Together, this study defines a spatial framework for ventricular patterning and maturation, providing a resource for investigating human cardiac development and disease.

Branched-chain amino acids play critical roles in cardiac physiology and diseases. Genetic deficiency in the valine catabolic enzyme ACAD8 is clinically associated with isobutyryl-CoA deregulation and cardiomyopathy in humans, but its roles in cardiac disease remain undefined. Here, we show that the levels of ACAD8 are reduced in humans and male mice with cardiac hypertrophy. Cardiomyocyte-specific Acad8 knockout in male mice exacerbates cardiac hypertrophy and cardiac dysfunction underwent pressure overload. Mechanistically, Acad8 deficiency leads to the accumulation of its substrate isobutyryl-CoA, which enhances histone isobutyrylation, chromatin accessibility and TEAD2 enrichment at promoter regions of hypertrophy-related genes, which increases the sensitivity to hypertrophic stress in mouse hearts and cardiomyocytes. Conversely, ACAD8 overexpression in cardiomyocytes suppresses isobutyryl-CoA accumulation and histone isobutyrylation, thereby attenuating cardiac hypertrophy and dysfunction. These results elucidate the roles of ACAD8 deficiency in cardiac diseases and reveal histone isobutyrylation in transcription regulation and cardiac pathology.

Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and reveal that disrupted redox oscillations are common diurnal alterations in organismal ageing. Restoring redox rhythms through the time-restricted application of antioxidants and pro-oxidants markedly improved glucose metabolism, motor performance and ageing-related characteristics of liver and skeletal muscle in male aged mice. Through multi-omics analyses we further reveal that restoring redox rhythms partially rejuvenates the hepatic transcriptome and chromatin accessibility in ageing-associated functional pathways and involves redox modification of CLOCK protein. Perturbing redox-sensitive cysteine 195 of CLOCK causes premature ageing phenotypes and hepatic reprogramming. Overall, our study reveals that redox rhythms ameliorate functional decline by modulating ageing-relevant reprogramming in liver and skeletal muscle and indicates that redox rhythm-based interventions might promote healthy ageing.

Despite its rapid economic rise over the past four decades, China now grapples with the challenge of accommodating and supporting its expanding aging population. In 2020, 18% of its population were over age 60, and 2.5% were over age 80, projected to rise to 39% and 10%, respectively, by 2050. This demographic shift places China at the forefront of diverse individual, familial and societal challenges. Here, we review these challenges in the context of emerging breakthroughs in basic and translational research, shifts in healthcare paradigms, evolving socioeconomic and political dynamics, and policy innovations. We synthesize China’s current policies toward promoting healthy longevity in the general population, focusing on social health insurance, long-term care insurance, community and home-based care and palliative care, as well as gerontological research, public health prevention, nutritional and medical interventions, while identifying strengths and gaps. Finally, we propose suggestions to promote a more inclusive, resilient and happier aging society within China’s distinctive sociopolitical and cultural context.

The global surge in the population of people 60 years and older, including that in China, challenges healthcare systems with rising age‐related diseases. To address this demographic change, the Aging Biomarker Consortium (ABC) has launched the X-Age Project to develop a comprehensive aging evaluation system tailored to the Chinese population. Our goal is to identify robust biomarkers and construct composite aging clocks that capture biological age, defined as an individual’s physiological and molecular state, across diverse Chinese cohorts. This Perspective outlines the core objectives, methodological framework and key deliverables of the X-Age Project, including cohort recruitment, standardized sample collection, multimodal data acquisition and clock model development. By integrating interdisciplinary expertise, we aim to provide a practical and scalable platform for understanding aging complexity and heterogeneity, early detection of accelerated aging and evaluation of aging interventions.

The mammalian heart exhibits transient but remarkable regenerative capacity during the early postnatal period, after which most cardiomyocytes exit the cell cycle. While the sirtuin family is well‐established as regulators of cell cycle progression, its specific role in cardiomyocyte proliferation and cardiac regeneration remains unclear. In this study, we found that Sirt4 expression increased during postnatal heart development. Adenovirus‐mediated Sirt4 overexpression in vitro inhibited cardiomyocyte proliferation by inducing oxidative DNA damage. Moreover, cardiomyocyte‐specific Sirt4 overexpression in vivo suppressed cardiomyocyte proliferation and impaired neonatal heart regeneration. Using Sirt4‐knockout mice, we found that Sirt4 deficiency promoted cardiomyocyte proliferation and extended the heart regeneration window. Furthermore, Sirt4 deficiency improved cardiac function and reduced myocardial fibrosis after ischaemia–reperfusion injury in adult mice. These findings establish Sirt4 as a critical regulator of cardiomyocyte proliferation and cardiac repair, suggesting that targeted Sirt4 inhibition may represent a promising therapeutic strategy for ischaemic heart diseases.