Post-translational modification (PTM) is an essential mechanism for enhancing the functional diversity of proteins and adjusting their signaling networks. The reversible conjugation of ubiquitin (Ub) and ubiquitin-like proteins (Ubls) to cellular proteins is among the most prevalent PTM, which modulates various cellular and physiological processes by altering the activity, stability, localization, trafficking, or interaction networks of its target molecules. The Ub/Ubl modification is tightly regulated as a multi-step enzymatic process by enzymes specific to this family. There is growing evidence that the dysregulation of Ub/Ubl modifications is associated with various diseases, providing new targets for drug development. In this review, we summarize the recent progress in understanding the roles and therapeutic targets of the Ub and Ubl systems in the onset and progression of human diseases, including cancer, neurodegenerative disorders, and heart diseases.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which represent the range of dystrophinopathies, account for nearly 80% of muscle dystrophy. DMD and BMD result from the loss of a functional dystrophin protein, and the leading cause of death in these patients is cardiac remodeling and heart failure. The pathogenesis and progression of the more severe form of DMD have been extensively studied and are controlled by many determinants, including microRNAs (miRNAs). The regulatory role of miRNAs in muscle function and the differential miRNA expression in muscular dystrophy indicate the clinical significance of miRNAs. This review discusses the relevant microRNAs as potential biomarkers and therapeutic targets for DMD and DMD cardiomyopathy as examples of dystrophinopathies.

Impaired calcium uptake resulting from reduced expression and activity of the cardiac sarco-endoplasmic reticulum Ca²⁺ ATPase (SERCA2a) is a hallmark of heart failure (HF). Recently, new mechanisms of SERCA2a regulation, including post-translational modifications (PTMs), have emerged. Our latest analysis of SERCA2a PTMs has identified lysine acetylation as another PTM which might play a significant role in regulating SERCA2a activity. SERCA2a is acetylated, and that acetylation is more prominent in failing human hearts. In this study, we confirmed that p300 interacts with and acetylates SERCA2a in cardiac tissues. Several lysine residues in SERCA2a modulated by p300 were identified using in vitro acetylation assay. Analysis of in vitro acetylated SERCA2a revealed several lysine residues in SERCA2a susceptible to acetylation by p300. Among them, SERCA2a Lys514 (K514) was confirmed to be essential for SERCA2a activity and stability using an acetylated mimicking mutant. Finally, the reintroduction of an acetyl-mimicking mutant of SERCA2a (K514Q) into SERCA2 knockout cardiomyocytes resulted in deteriorated cardiomyocyte function. Taken together, our data demonstrated that p300-mediated acetylation of SERCA2a is a critical PTM that decreases the pump’s function and contributes to cardiac impairment in HF. SERCA2a acetylation can be targeted for therapeutic aims for the treatment of HF.

Background: National Health Insurance Herbal prescriptions (NHPs) are widely used; however, their multi-component composition complicates mechanistic interpretation and impedes the development of evidence-based approaches in traditional medicine and healthcare policy. In this study, we applied a systems biology approach to link molecular mechanisms to clinical effects. Methods: From 56 NHPs, 13 with sufficient clinical evidence were selected. Multi-layer networks connecting herbs, ingredients, genes, and diseases were constructed using SymMap, with interactions filtered for oral bioavailability and statistical significance (false discovery rate < 0.05). Network-predicted diseases were validated against a clinically validated benchmark using permutation-based null model analysis, and gene set enrichment analysis (GSEA) was used to identify key molecular pathways. Results: Networks predicted an average of 1359 diseases per NHP, reflecting their polypharmacology. Importantly, the overall predicted disease sets for 10 of 13 NHPs showed statistically significant overlap with known clinical uses (p < 0.05, several with p < 0.001). GSEA indicated that NHPs commonly modulate three biological axes—hormone–metabolic regulation, neural signaling, and cell proliferation control. Conclusions: NHPs act as potential systemic homeostasis regulators. Our study introduces a computationally validated framework integrating network pharmacology with permutation-based statistical testing, providing a data-driven rationale for NHP use. These computational findings are exploratory and require future biological and clinical validation.

Background: Predicting the molecular mechanisms and therapeutic effects of National Health Insurance herbal Prescriptions (NHPs) is challenging because of their multi-compound nature. We aimed to predict the therapeutic mechanisms of 56 NHPs using a Traditional Chinese Medicine (TCM) database and bioinformatic tools. Methods: We used a TCM database and bioinformatic techniques to construct networks of 56 NHPs. The network’s predicted potential therapeutic symptoms were compared with clinical study results and known indications to evaluate their validity. Finally, we identified the potential diseases and predicted the molecular mechanisms of 13 selected NHPs. Results: Of the initial 56 NHPs, 13 were selected for a detailed analysis. A five-layer network was constructed, which linked an average of 1,359 potential diseases per prescription. The concordance rate between network predictions and clinical papers was 45.6%, whereas that between network predictions and previously known major indications was 37.8%. Molecular mechanism analysis revealed that NHPs affect multiple pathways, including those related to metabolic diseases and nerve regulation. Conclusion: Our findings suggest that combining bioinformatics and clinical data can provide insights into the therapeutic effects of NHPs. This approach can guide future research by predicting potential therapeutic mechanisms and applications, providing insights into the therapeutic effects of NHPs.