Glycogen synthase 1 (GYS1) is the rate-limiting enzyme responsible for glycogen synthesis in skeletal muscle, heart, brain, and other extrahepatic tissues, playing a central role in systemic energy homeostasis. The human GYS1 gene maps to chromosome 19q13.33, comprises 16 exons, and encodes a 737-amino-acid polypeptide that is highly conserved across mammals. GYS1 activity is subject to multilayered and precisely coordinated regulation. At the transcriptional level, the GYS1 promoter contains a hypoxia response element (HRE) that mediates HIF-1α-dependent induction under low-oxygen conditions, as well as a muscle-specific enhancer harboring MEF2 and MyoD binding sites that confers tissue-restricted expression. At the post-translational level, a hierarchical phosphorylation cascade serves as the primary activity switch: glycogen synthase kinase 3β (GSK3β) sequentially phosphorylates four C-terminal serine residues following casein kinase II priming, while protein kinase A (PKA) and AMP-activated protein kinase (AMPK) provide parallel inhibitory inputs at both N- and C-terminal sites. Dephosphorylation and reactivation are mediated by protein phosphatase 1 (PP1) through tissue-specific glycogen-targeting regulatory subunits such as PPP1R3A and PPP1R3B, which anchor PP1 to glycogen particles and direct its activity toward GYS1. The allosteric activator glucose-6-phosphate (G6P) binds at the dimer interface, simultaneously enhancing catalytic efficiency and promoting dephosphorylation susceptibility, thereby establishing a feed-forward activation loop that couples substrate availability to glycogen synthesis. Beyond phosphorylation, GYS1 is regulated by ubiquitination (mediated by the E3 ligase PJA1), acetylation, O-linked β-N-acetylglucosamine (O-GlcNAc) modification, and SUMOylation, which collectively modulate protein stability, subcellular localization, and protein-protein interactions. Epigenetic mechanisms, including CpG island methylation and histone acetylation dynamics, govern chromatin accessibility at the GYS1 locus, while muscle-specific microRNAs such as miR-1 and miR-206 fine-tune GYS1 expression at the post-transcriptional level. Dysregulation of GYS1 has been identified as a central pathogenic driver in a spectrum of human diseases. In inherited glycogen storage disorders—including Lafora disease, adult polyglucosan body disease (APBD), and Pompe disease—loss of upstream regulatory control leads to GYS1 hyperactivation and the accumulation of structurally abnormal or excessive glycogen, resulting in progressive neurodegeneration, myopathy, and multiorgan dysfunction. In type 2 diabetes mellitus (T2DM), impaired insulin signaling through the PI3K-AKT-GSK3β axis maintains GYS1 in a hyperphosphorylated inactive state in skeletal muscle, compromising postprandial glucose disposal and exacerbating hyperglycemia. In oncology, GYS1 exhibits context-dependent roles across multiple cancer types. In hepatocellular carcinoma, FMO2⁺ cancer-associated fibroblasts stabilize GYS1 by competitively inhibiting PJA1-mediated ubiquitination, and stabilized GYS1 subsequently activates NF‑κB/CCL19 signaling to promote tertiary lymphoid structure formation and enhance anti-PD-1 immunotherapy responsiveness. In clear cell renal cell carcinoma, GYS1 promotes tumor progression through non-canonical NF‑κB pathway activation via the scaffold protein RPS27A. In triple-negative breast cancer, GYS1 has been identified as a trigger of disulfidptosis and an activator of NF-κB signaling through non-enzymatic facilitation of IκBα degradation. In colorectal cancer, mitochondrial fission deficiency drives AMPK-dependent GYS1 upregulation and glycogen accumulation as a compensatory survival mechanism, while in cervical cancer, GYS1-maintained glycogen reserves fuel the pentose phosphate pathway to generate NADPH for ROS clearance, thereby conferring cisplatin resistance in cancer stem cells. Therapeutic strategies targeting GYS1 have gained substantial momentum across these disease contexts. For glycogen storage disorders, antisense oligonucleotides, small interfering RNAs (e.g., ABX1100), and small-molecule inhibitors (e.g., MZ-101) have demonstrated preclinical and early clinical efficacy in reducing pathological glycogen accumulation. For T2DM, pharmacological activation of GYS1 through GSK3β inhibition or enhancement of PP1-mediated dephosphorylation is being explored to restore insulin-stimulated glycogen synthesis. In cancer, GYS1-directed interventions—including targeted silencing to sensitize tumors to chemotherapy and immune microenvironment modulation to enhance immunotherapy—represent emerging precision oncology approaches. This review provides a comprehensive and integrated account of GYS1 gene structure, tissue-specific distribution, regulatory networks, and pathogenic roles in metabolic disorders and malignancies, with the aim of establishing a theoretical framework for the development of GYS1-targeted precision therapies.

OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

Readiness for Hospital Discharge(RHD)refers to a multidimensional assessment of a patient's ability to transition safely from hospital to home,encompassing physiological stability,psychological preparedness,and social support adequacy.For patients requiring Home Nutrition Support(HNS),discharge readiness is particularly critical due to their heightened need for post-discharge specialized care,which significantly influences long-term recovery and quality of life.This paper reviews the concept,influencing factors,and unmet needs of RHD in patients with HNS and proposes targeted strategies to enhance discharge preparedness.By addressing gaps in current practices,we aim to optimize RHD in this vulnerable population and provide clinicians with evidence-based guidance for developing effective discharge plans.

Objective To explore the differences in positive psychological resources among elementary and secondary school students with and without non-suicidal self-injury(NSSI)behaviors.Methods Between September and October 2023,the assessment data of 56 870 students aged 9 to 18 years in Chengdu,Sichuan Province were collected.The R software package was used to evaluate the network structure and symptom centrality,and the global strength and structural differences of the networks of students with and without NSSI behaviors in elementary,junior high,and senior high schools were compared.Results The prevalence of NSSI among elementary and secondary school students stands at 12.21%.Specifically,it peaks in junior high school students,reaching 14.22%,followed by that in senior middle school students at 13.66%,and is lowest in elementary school students at 10.17%.Regarding the network structure in elementary school students,irrespective of the presence or absence of NSSI behavior,subjective support exhibits the strongest network strength,and family functioning demonstrates the highest closeness centrality.Among junior high school students without NSSI behaviors,the strongest network strength was observed in subjective support,whereas for those with NSSI behaviors,self-esteem showed the strongest network strength.In addition,subjective support exhibited the highest closeness centrality in both groups.In senior high school students,self-esteem was the factor with the strongest network strength for students with or without NSSI behaviors.For senior high school students without NSSI,subjective support had the highest closeness centrality,while for those with NSSI,expressive suppression showed the highest closeness centrality.The edge weights differed significantly among elementary school students in family functioning-self-esteem(E=0.093)and family functioning-objective support(E=0.087).For junior high school students,significant differences were found in objective support-subjective support(E=0.131)and family functioning-impulse control(E=0.109).Among senior high school students,significant differences were observed in impulse control-family function(E=0.133)and subjective support-utilization of support(E=0.130)(P<0.05).Conclusion Excessive family involvement in elementary school students and expressive suppression in senior high school students may be important influencing factors for NSSI behaviors.The lack of social support has a greater impact on junior and senior high school students.The strength of the connection among subjective support,objective support,and utilization of support is an important indicator.

Depression is a highly heterogeneous psychiatric disorder with complex pathogenesis influenced by the interplay of biological,psychological,and social-environmental factors.Based on the 2021 edition of the Chinese Guidelines for the Prevention and Treatment of Depressive Disorders,which explicitly identify gender as a significant risk factor for depression onset,this paper systematically reviews the gender-differentiated pathogenesis and therapeutic advances in depression from both traditional Chinese medicine(TCM)and Western medical perspectives.In Western medicine,a large number of studies have demonstrated the sex-specific mechanism of estrogen/testosterone fluctuations and monoamine transmitter system regulation.While in TCM,although the constitution theory proposes that there are significant gender differences in congenital constitution and that qi depression and qi deficiency are associated with susceptibility to depression,current evidence primarily relies on cross-sectional surveys and lacks validation through high-quality RCTs.Compared with Western medicine,the direct research on gender-differentiated antidepressant effects in TCM remains relatively underdeveloped.In future study,it may be possible to deepen and improve the research on anti-depression in TCM from the biological markers of particular constitutions in the gender dimension.This paper advocates establishing a bio-psycho-social integrated intervention model,advancing mechanistic exploration through prospective cohort studies and multi-omics technologies,and promoting precision diagnosis and treatment systems based on gender differences,and to form a three-dimensional diagnosis and treatment and research system that covers biomarkers,social role assessment,and TCM constitution identification,in order to provide a new theoretical framework and a practical pathway for the precise medical treatment of depression.

The lab module of exploratory experiment is newly designed in the practical course of bio-chemistry.Here we describe one of the experimental projects,and it originates from new scientific re-search results on the dynamic structure of ATP synthase.This exploratory experiment is organized in the form of real scientific research,which would fully mobilize the initiative and creativity of students in learning theoretical knowledge and experimental technology.Students work in groups and start with refer-ence reading.Through cooperation,they must develop certain experimental plan,handle samples with photocrosslinking technique and utilize the high-throughput electrophoresis method to analyze the dynamic structural change of ε subunit in ATP synthase under different physiological conditions.High quality re-sults from high-throughput electrophoresis can only be obtained through optimized operation and treat-ment,from which students would experience the process of technological innovation.The teaching process of this lab module embodies the student-centered teaching concept and is widely approved and supported by students.The project of ATP synthase closely combines the content of lab course with cut-ting-edge technology.Students can deeply experience the importance of experimental technology innova-tion in solving scientific problems.The practical ability of students would be comprehensively improved through this lab module.

Aim To explore the therapeutic effect and mechanism of Qingjie Huagong decoction in modulating PI3K/AKT/NF-κB signaling pathway in inflammatory response of acute pancreatitis(AP)mice.Methods Twenty-four mice were randomly divided into Blank group,Model group,Ustekin group,and Qingjie Hua-gong decoction group,with six mice in each group.The AP model was prepared by using rain frogin.Serum α-AMS,PNLP,IL-1β,IL-6,IL-8,IL-18,and TNF-α lev-els were detected by ELISA;the pancreatic pathology was detected by HE staining;the expressions of PI3K,AKT,and NF-κB-related proteins and mRNAs were de-tected by immunohistochemistry,Western blot,and RT-qPCR.Results Compared with the blank group,the model group showed obvious pathological damage to the pancreas,with significantly higher serum α-AMS,PN-LP,IL-1β,IL-6,IL-8,IL-18,and TNF-α levels(P＜0.01),and significantly higher levels of PI3K,AKT,and NF-κB-related proteins and mRNA expression(P＜0.01).Compared with the model group,both the Qingjie Huagong decoction group and the ustekin group improved the histopathological changes in the pancreas of AP mice,decreased the serum α-AMS,PNLP,IL-1β,IL-6,IL-8,IL-18,and TNF-α levels,and down-reg-ulated the expression levels of pancreatic PI3K,AKT,NF-κB-related proteins and mRNA(P＜0.05 or P＜0.01).Conclusion Qingjie Huagong decoction may inhibit the inflammatory response and protect pancreat-ic tissues by regulating the expression of PI3K/AKT/NF-κB signaling pathway.

The lab module of exploratory experiment is newly designed in the practical course of bio-chemistry.Here we describe one of the experimental projects,and it originates from new scientific re-search results on the dynamic structure of ATP synthase.This exploratory experiment is organized in the form of real scientific research,which would fully mobilize the initiative and creativity of students in learning theoretical knowledge and experimental technology.Students work in groups and start with refer-ence reading.Through cooperation,they must develop certain experimental plan,handle samples with photocrosslinking technique and utilize the high-throughput electrophoresis method to analyze the dynamic structural change of ε subunit in ATP synthase under different physiological conditions.High quality re-sults from high-throughput electrophoresis can only be obtained through optimized operation and treat-ment,from which students would experience the process of technological innovation.The teaching process of this lab module embodies the student-centered teaching concept and is widely approved and supported by students.The project of ATP synthase closely combines the content of lab course with cut-ting-edge technology.Students can deeply experience the importance of experimental technology innova-tion in solving scientific problems.The practical ability of students would be comprehensively improved through this lab module.