Medication adherence is critical to long-term graft and patient survival after liver transplantation (LT), yet the effectiveness of adherence-promoting interventions across the post-transplant survivorship continuum remains uncertain. We systematically reviewed interventions to improve medication adherence including immunosuppressive regimen simplification, pharmacist-led or counseling strategies, behavioral and multicomponent programs, and technology-based interventions. We identified 33 studies: immunosuppressive regimen simplification (n=8), pharmacist-led or counseling strategies (n=6), behavioral or multicomponent programs (n=3), virtual visits/remote monitoring (n=9) and mobile or text-based tools (n=7). In pooled analyses of randomized trials, active interventions improved adherence versus usual care (OR 4.04, 95% CI 1.94-8.41), although heterogeneity was substantial. A higher prevalence of alcohol-associated liver disease was associated with weaker intervention effects. Regimen simplification, especially conversion from twice-daily to once-daily tacrolimus, showed consistent improvement in adherence while maintaining acceptable graft outcomes. Pharmacist-led interventions improved medication knowledge, dosing compliance, and drug monitoring. Telehealth interventions reduced travel burden and, in some studies, early readmissions and hospital stay. Overall, regimen simplification and structured multidisciplinary support appear most effective, but larger longitudinal trials with standardized adherence measures are needed.

Tacrolimus (TAC) nephropathy is a major complication of immunosuppressive therapy and contributes to chronic kidney disease (CKD) progression through ischemia, metabolic dysfunction, and oxidative stress; however, its protein-level basis remains unclear. This study sought to identify characteristic molecular alterations in renal cortices of TAC-treated mice, so as to clarify the link between replication stress responses and metabolic dysfunction. A previously generated proteomic dataset from a TAC-induced chronic nephrotoxicity mouse model was analyzed using a protein-centered analytical strategy, including statistical, Gene Ontology, pathway, upstream regulator, and disease-enrichment analyses. A total of 7466 proteins were quantified. Upregulated proteins included KAT6A and NCKAP1, whereas downregulated proteins included NDUFC2, HSD17B12, and TECR. Coordinated impairment of CoQ10-dependent and glutathione-dependent antioxidant defenses was identified, reflected by reductions in AIFM2 (FSP1) and GSTA4/GSTT2. Enrichment analyses indicated activation of MCM- and ATR-associated replication stress responses in the upregulated group, and impaired lipid metabolism, CoA biosynthesis, mitochondrial function, and redox regulation in the downregulated group. TAC nephropathy is characterized by two major molecular signatures: central disruption of antioxidant defense systems, spanning FSP1-mediated CoQ10 regeneration and GST- associated antioxidant systems, together with suppression of lipid and energy metabolism and activation of replication stress responses. These findings provide a protein-level molecular framework linking coordinated impairment of antioxidant defense systems, suppression of lipid and energy metabolism, and activation of replication stress responses in TAC-induced chronic nephrotoxicity. These findings also suggest the FSP1 pathway, GST-associated antioxidant systems, and CoA-dependent metabolism as potential therapeutic targets for CKD progression.

Cancer-related fatigue (CRF) remains difficult to manage, and the impact of metal ion-regulated cell death on peripheral fatigue during anticancer therapy is unclear. Here, we investigated whether ferroptosis inducers (FINs) potentiate copper ionophore (CIN)-triggered cuproptosis in skeletal muscle and aggravate lung cancer-related fatigue (LCaRF), and evaluated redox-based interventions. LCaRF cellular models were established using C2C12 exposed to LLC/M109 tumor-conditioned supernatants and treated with FINs (sorafenib/erastin) plus CIN + CuCl2 (CIN-Cu + FINs). Cell viability, lipid peroxidation, DLAT aggregation (cuproptosis hallmark), copper/glutathione (GSH), mitochondrial function, and FKBP5/Nrf2-HO-1 signaling were assessed with pharmacologic and genetic modulation. An orthotopic lung cancer mouse model underwent wheel-running, tail suspension, and open-field testing with tetrathiomolybdate (TTM) or hydrogen as interventions. FINs sensitized C2C12 cells to CIN-Cu cytotoxicity and increased DLAT aggregation; copper chelation with TTM attenuated these effects. FINs depleted GSH and amplified mitochondrial dysfunction/ROS; exogenous GSH or hydrogen reduced DLAT aggregation and restored mitochondrial indices. FKBP5 was markedly upregulated by CIN-Cu + FINs and linked to suppressed antioxidant defense (Nrf2/HO-1). In vivo, CIN-Cu + FIN treatment exacerbated fatigue-like behaviors, while TTM or hydrogen partially improved performance. FIN-CIN combinations may aggravate skeletal muscle injury and fatigue-like phenotypes in LCaRF models by promoting cuproptosis via GSH depletion and FKBP5/Nrf2-HO-1 dysregulation.

Selecting the most relevant models for model-informed precision dosing (MIPD) remains challenging, particularly when numerous population pharmacokinetic (popPK) models are available, making external evaluation of all candidates time- and resource-consuming. We aimed to develop and assess an adaptable relevance-based scoring methodology, illustrated with tacrolimus in adult transplant recipients. Candidate criteria were derived from published guidelines and external evaluations. A 23-item relevance score was developed, covering training dataset, study design, evaluation methodology, covariates, and parameter precision. For tacrolimus, a systematic literature review identified 28 models which were scored for relevance and externally evaluated using an independent dataset from Rennes University Hospital (86 patients). Predictive performances were assessed at individual and population levels using bias and imprecision metrics. Predicted and observed AUCs were compared against therapeutic thresholds. Models were then ranked using an external evaluation score (maximum 14 points) based on predefined acceptance limits for bias and imprecision. Correlations between relevance-based and external scores and ranks were assessed using Pearson and Spearman correlations. The mean relevance score was 22.3/56 (range: 6-38). Higher scores were associated with larger and richer datasets, prospective or multicentric designs, inclusion of clinically relevant covariates, and precise parameter estimates. Individual predictions showed acceptable bias and imprecision, whereas population predictions were consistently inaccurate. AUC concordance (56%-94%) was mainly limited by overestimation. Highest external score was 6/14. Correlation between relevance-based and external scores was moderate (Pearson = 0.56; Spearman = 0.61). This work provides a structured basis for popPK model selection and identified tacrolimus models suitable for MIPD applications.