Primary liver cancer (PLCa) is a highly malignant tumor with a ranking sixth incidence rate and ranking third mortality worldwide, and its molecular mechanism has not been fully clarified with only moderate progress yet made for an effective overall disease management in the framework of predictive preventive personalized medicine (PPPM; 3PM). Protein ubiquitination is involved in the entire pathophysiological process of PLCa being associated with other integrative molecular profiles such as transcriptome and proteome. We hypothesize here that protein ubiquitination profile and its associated molecular profiles in human PLCas differ from control human liver tissues. This study aimed to use ubiquitinome-centered multiomics to identify effective ubiquitination-related molecular patterns as a candidate molecular basis for future predictive approaches, targeted prevention, and personalized medical services at the early stages of human PLCas. Quantitative ubiquitinomics globally diagnose the ubiquitination profiles and differentially ubiquitinated proteins (DUPs) in PLCas (n = 10) compared to control liver tissues (n = 10), followed a series of analysis in cellular components (CCs), biological processes (BPs), molecular functions (MFs), signaling pathways, and protein-protein interaction (PPI) networks. DUP data were combined with differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) to identify integrative molecular patterns, overall survival-related DUPs, and hypothesis-generating drug-sensitivity DUPs for PLCa. A total of 481 DUPs with 819 differentially ubiquitinated tryptic peptides (DUTPs) were identified, including 188 DUPs with decreased ubiquitination levels and 293 DUPs with increased ubiquitination levels. These DUPs are significantly involved in 89 BPs, 64 CCs, 59 MFs, and 57 signaling pathways such as proteasome-related signaling pathways, programmed cell death-related signaling pathways, energy metabolism-related signaling pathways, drug metabolism-related signaling pathways, fatty acid degradation, steroid hormone biosynthesis, primary bile acid biosynthesis, and lipid metabolism-related signaling pathways. PPPI analysis of 481 DUPs identified 56 pairs of high-reliable co-expression molecules such as CYP2A6 and CYP2A7, HBA1 and HBB, RPS20 and RPS27A, and RPLP0 and RPS3, which are mainly involved in ribosome and proteasome-related signaling pathways. Further, the relationship analysis between DUPs and DEGs, between DUPs and DEPs, and among DUPs, DEGs and DEPs deeply revealed the high diversities of molecule events in PLCas. Moreover, uniquitinome-centered multiomics identified 105 overall survival-related DUPs and 43 drug sensitivity-related DUPs. The presented study provides the first ubiquitination landscape and biomarker-sets for systematic examinations of the molecular pathways of PLCas. These findings aid in the identification of novel pharmaceutical agents and targets such as hypothesis-generating drug sensitivity-related DUPs (ALDOB, CDO1, COL15A1, CYP27A1, CYP2C9, CYP2E1, CYP4A11, CYP4F2, CYP8B1, DAO, FGA, IQGAP2, MPDZ, RDH16, SORD, and XDH), and the development of robust biomarkers such as DUP ezymes (TRIM21, UBA7, RNF213, UBR2, DTX3L, TRIM47, VCPIP1, and NEDD8), as the candidate molecular basis for optimizing the overall management of liver cancers by implementing 3PM conceptual and technological innovation.
Liver fibrosis is the core pathological precursor stage in the development of cirrhosis and hepatocellular carcinoma. Its progression depends on complex pathological mechanisms, including multicellular interactions, metabolic reprogramming, and microenvironmental disturbances, placing a heavy burden on global public health systems. Traditional clinical diagnosis and treatment are primarily based on a passive, reactive medical model, with significant limitations such as delayed diagnosis, single-mode intervention, and insufficient personalization. Recent studies have confirmed that mitochondrial homeostasis imbalance is a key upstream driver mediating hepatic stellate cell activation and the pathological progression associated with liver fibrosis. Mitochondria can serve as critical systemic biosensors in the human body, enabling early disease warning and health-status assessment through noninvasive body-fluid testing, such as tear analysis and circulating mitochondrial DNA detection. This provides new targets and an evaluation system for precise intervention based on 3PM (predictive, preventive, and personalized medicine). This article systematically reviews the core molecular pathological mechanisms of liver fibrosis, comparatively analyzes the application bottlenecks of traditional single-targeted nanostrategies, and highlights the unique advantages of “dual-targeted nanodelivery systems” in repairing mitochondrial dysfunction and remodeling the hepatic microenvironment. Furthermore, this article proposes a new three-tiered precision intervention strategy for liver fibrosis guided by the 3PM concept. At the primary health prevention and control level, mitochondrial homeostasis monitoring is used to enable early prediction in high-risk populations and prevent the transition from health to disease. At the secondary clinical intervention level, precise nao-targeted therapy is employed to inhibit the continued progression of fibrosis. At the tertiary rehabilitation management level, individualized diagnosis and treatment are used to improve patient outcomes and reduce the risk of complications. Compared with traditional passive treatment approaches, mitochondria-based dual-targeted nanomedicine combines diagnostic innovation, preventive cost-effectiveness, and therapeutic personalization. It is a novel clinically translatable strategy that aligns with the paradigm of 3PM and may efficiently reverse liver fibrosis, offering excellent prospects for clinical application and substantial health-economic value.
Male health is much more than only an essential pillar of the sustainable socio-demographic development of each society. To this end, erectile dysfunction, preventable male infertility, and urological cancers (including testicular, bladder, kidney, prostate, and penile ones) represent a serious health problem and well-recognized subject to change the healthcare paradigm from reactive to proactive medical services. For example, most frequently recorded complains of urological cancer survivors, who underwent aggressive oncological treatments, include chronification of pain, reduced physical activity, chronic fatigue, disordered sleep, and severe mental health problems, which per evidence are related to mitochondrial stress and compromized mitochondrial fitness to be essentially considered by innovative rehabilitation programs. Case reports of affected patients presented in this article illustrate significant deficits attributable to the reactive medicine in primary (protectioevidence are related to mitochondrial stress and cn of individuals at the suboptimal health level from health-to-disease transition), and secondary (protection of affected patients from disease progression) care. Herewith we in-depth analyse currently unmet patient needs and provide 3PM (predictive preventive personalized medicine)-guided recommendations to advance primary and secondary care in the area of the sustainable male health. The proposed innovation integrates multi-professional expertise, population screening programs dedicated specifically to suboptimal health conditions, predictive holistic phenomapping, patient stratification, health risk assessments utilizing biomarkers of mitochondrial homeostasis in the tear fluid as a non-invasive diagnostic tool, lifestyle adjustments, and tailored nutraceuticals, among others.
Chronic pelvic pain syndrome (CPPS) encompasses a heterogeneous group of debilitating conditions including interstitial cystitis/bladder pain syndrome (IC/BPS), chronic abacterial prostatitis, endometriosis, and pelvic congestion syndrome, among others. Despite advances in symptomatic management, CPPS remains challenging due to its multifactorial etiology, complex phenotypes, and poor response to conventional reactive treatments. On the other hand, sympathetic overdrive phenotype (SOP) carriers frequently suffer from increased stress sensitivity, chronic sterile inflammation, pain chronification, and mitochondrial stress – all considered the key CPPS/SOP shared pathomechanisms. Further, the dominant vasoconstriction, altered sense regulation (e.g. the reduced feeling of thirst potentially resulting in systemic dehydration) as well as altered multi-drug resistance protein profiles characteristic for SOP (e.g. exemplified by the Flammer syndrome) may predispose affected individuals to the therapy resistance such as CPPS patients with vulvar-vaginal dryness and abacterial prostatitis. This review article highlights the central role of SOP, systemic mitochondrial stress as well as gut and urinary microbiome alterations – all, per evidence, are considered systemic modifiable risk factors of the CPPS manifestation, disease progression, and therapy resistance. The article introduces 3PM-guided patient-centered solutions aiming to improve life quality and individual outcomes in the CPPS patient cohort. Non-invasive mitochondria-based biosensorics, e.g. applied via the tear fluid analysis, and digital health monitoring, per evidence, enable early health risk assessment and patient stratification at the level of reversible damage to health. Recommended targeted preventive strategies encompass individually adapted lifestyle modifications, modulation of the stress-associated mitochondrial homeostasis, and application of supportive nutraceuticals. Personalized 3PM-guided treatment algorithms transform CPPS management into the patient-centered, cause-oriented and cost-effective proactive care, protecting vulnerable individuals against health-to-disease transition and preventing disease progression in stratified patients.
