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Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.

For many years, androgen deprivation therapy (ADT) alone was considered the established standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). A paradigm shift was initiated by the CHAARTED trial, which for the first time demonstrated a significant overall survival benefit with the addition of docetaxel to ADT. Further randomized trials also revealed a clinical benefit from intensifying ADT with the modern hormonal agents abiraterone, apalutamide, darolutamide and enzalutamide. Moreover, the triplet combination of darolutamide, ADT and docetaxel was shown to provide a survival advantage compared with chemo-hormonal therapy alone. These combination approaches are now considered the standard of care in mHSPC. Although the introduction of these treatment strategies has substantially prolonged median overall survival in patients with mHSPC, a considerable proportion of patients still experience early mortality during the course of the disease. Consequently, a significant unmet need for novel therapeutic options remains. This article aims to review first-line treatment options in the mHSPC setting and highlight their differences to support evidence-based therapeutic decision-making. In addition, emerging developments are discussed with the goal of further improving clinical outcomes.

ABSTRACTBackground and ObjectiveVesicourethral anastomotic stenosis and/or urethral stenosis (VUAS/US) is a complication of robotic‐assisted radical prostatectomy (RARP) for prostate cancer. We aimed to evaluate the incidence of VUAS/US after RARP and to identify potential risk factors.Materials and MethodsWe performed a retrospective assessment of clinical records of patients with RARP as primary prostate cancer treatment (January 2011–December 2018) and investigated associations between VUAS/US formation and radiotherapy, pT‐stage, tumor margins, Gleason score, nerve‐sparing, and postoperative duration of bladder catheterization. Statistical analysis was performed via uni‐ and multivariable cox regression; risk estimation was done with the Kaplan–Meier method and log‐rank test.Results and Limitations809 patients were included in the study. Median clinical follow‐up was 61.0 months (IQR 50.0–75.0) and 175 (22%) patients received radiotherapy. VUAS and US were recorded in 19 (2.3%) and 10 (1.2%) patients, respectively. Whereas in univariable analysis radiotherapy, pT‐stage ≥ pT3a, higher Gleason score, positive tumor margins, nerve‐sparing, and prolonged duration of bladder catheterization were significant risk factors, in a multivariable analysis only radiotherapy (p = 0.003) and prolonged duration of bladder catheterization (p = 0.0309) proved to be independently predictive. Estimated 5‐year risk of VUAS/US formation was lower without than with radiotherapy (2.1% [95% CI: 0.9–3.3] vs. 7.3% [95% CI: 3.4–11]) and with normal compared to prolonged bladder catheterization (2.6% [95% CI: 1.4–3.8] vs. 9.9% [95% CI: 2.3–18]). Retrospectivity and the limited number of events were our major limitations.Conclusions and Clinical ImplicationsLow incidence of VUAS/US in RARP. Patients undergoing radiotherapy or requiring prolonged catheterization should be explicitly informed about the risk of VUAS/US and about symptoms. Also, physicians must be aware.

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a genetically-driven disorder with a broad spectrum of cardiac manifestations, ranging from asymptomatic cases to severe heart failure. ACM is often associated with genetic variations in desmosomal proteins, particularly plakophilin 2 (PKP2). Some clinically affected individuals experience 'hot phases' resembling acute myocarditis. The role of external factors, such as viral infections, in ACM onset and progression remains elusive. Therefore, we examined the effects of murine cytomegalovirus (MCMV) infection on ACM using mice with heterozygous cardiomyocyte-specific Pkp2 deficiency (Pkp2+/-), which exhibited no baseline differences compared to wild type (Ctr) mice. Methods and Results Pkp2+/- and Ctr mice were infected with MCMV or PBS to assess cardiac structure, function and immune response at various time points post-infection. Acute infection (5-14 days) induced immune cell aggregates in myocardial tissues, comprising cytotoxic CD8+ and CD4+ T cells, irrespective of genotype. Although viral DNA load diminished over time, it persisted up to 6 months post-infection (6mpi). Our hypothesis proposing inflammation-mediated myocardial damage was supported as systolic dysfunction occurred at 3mpi, progressively worsening in Pkp2+/- MCMV, but not in Ctr MCMV hearts. Notably, fibrosis was absent in cardiac tissue, but immune cell infiltration predominated. Besides the anticipated CD8+ T-cell accumulation, we observed significantly increased monocytes/macrophages, exclusively in Pkp2+/- MCMV mice. Single-cell RNA seq revealed distinct immune cell sub-clusters, including Ly6Chi monocytes and pro-fibrotic macrophages, particularly in Pkp2+/- MCMV mice. These populations were also present in Pkp2+/- hearts without infection, indexing a subclinical effect of the Pkp2 mutation and involvement of macrophages in the early disease response. Importantly, cytokine analyses from heart lysates and serum samples indicated an upregulation of pro-inflammatory cytokines and chemokines (e.g. IL-1ß, CCL2) in a genotype-dependent manner. Further immune cell analyses in homozygous Pkp2 knockout (Pkp2-/-) mice, exhibiting pronounced immune cell infiltrations at an early stage, demonstrated a shift from tissue-resident (TIM4+ MHCII-) to pro-inflammatory (TIM4- MHCII+) and tissue-injury-associated macrophages (TIM4- MHCII-), suggesting activated states and mediator secretion exacerbating tissue damage as crucial factors in ACM. Conclusion The heterogeneous clinical presentations of ACM may result from the interplay between genetic susceptibility and immune responses. Our study highlights that compromised desmosomes, combined with an inflammatory trigger like MCMV infection, can initiate cardiac dysfunction, likely through exaggerated immune activation and progressive tissue damage. Furthermore, specific targeting of migrating monocytes might modulate the pro-inflammatory response, potentially slowing ACM development.

Barth syndrome is a mitochondrial disorder caused by Tafazzin (TAZ) mutations, which impair cardiolipin remodelling and contribute to systemic metabolic alterations. While islet dysfunction has been implicated in Barth syndrome, its underlying mechanisms remain unknown. We aimed to determine how Tafazzin (Taz) deficiency affects mouse pancreatic islet metabolism and hormone secretion, and whether systemic signals, such as circulating factors, modulate these effects in vivo. In vivo and in vitro models were used to separate direct islet effects from systemic influences of Taz deficiency. We used a mouse model of global Taz knockdown (Taz-KD) and combined in vivo and in vitro approaches to assess pancreatic islet metabolism, morphology and hormone secretion. Islet function was evaluated under basal and glucotoxic conditions. Transcriptomic profiling was performed to identify gene expression changes in isolated islets from Taz-KD mice and following in vitro Taz-KD. Additionally, we examined the role of the circulating factor fibroblast growth factor 21 (FGF-21) in modulating islet function. Despite impaired cardiolipin remodelling, pancreatic islets from Taz-KD mice maintained insulin secretion, supported by compensatory mechanisms such as increased glucose uptake, expanded mitochondrial volume and increased metabolic parameters. In addition, alpha cell mass and glucagon secretion were significantly increased in Taz-KD islets. These islet-specific adaptations occurred alongside improved whole-body glucose tolerance, elevated circulating FGF-21 levels and enhanced glucose uptake in brown adipose tissue. In contrast, in vitro Taz-KD led to impaired islet function and reduced insulin secretion. Transcriptomic analysis revealed distinct gene expression patterns between in vivo and in vitro Taz-KD models. While in vivo upregulation of genes related to N-acetylglucosamine biosynthesis and O-GlcNAcylation were related to compensatory mechanisms, in vitro Taz-KD affected, among others, the MAPK pathway, contributing to islet dysfunction. Notably, islet incubation with FGF-21 was able to restore insulin secretion after in vitro Taz-KD. Our findings demonstrate that while Taz and cardiolipin remodelling are essential for beta cell physiology, systemic and islet-specific compensatory mechanisms preserve insulin secretion in vivo in Taz-KD mice, alongside increased glucagon secretion. These adaptations probably contribute to the altered metabolic phenotype observed in Barth syndrome and highlight a potential role for hormones and circulating factors such as FGF-21 in maintaining islet function and glucose homeostasis.

BackgroundPheochromocytoma and paraganglioma are neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively. Most cases of metastatic pheochromocytoma and paraganglioma are driven by dysregulation of the hypoxia-inducible factor 2α (HIF-2α) pathway. Belzutifan is a HIF-2α inhibitor that may provide antitumor activity in patients with advanced pheochromocytoma or paraganglioma.MethodsWe conducted a phase 2, international, single-group trial involving 72 participants with locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent treatment. Participants received belzutifan at a dose of 120 mg once daily until the occurrence of progression, unacceptable toxic effects, or withdrawal from the trial. The primary end point was confirmed objective response (complete or partial response) as assessed by blinded independent central review. Secondary and other key end points included the duration of response, disease control, progression-free survival as assessed by blinded independent central review, overall survival, safety, and a reduction from baseline in antihypertensive medication.ResultsAt a median follow-up of 30.2 months (range, 23.3 to 37.6), the percentage of participants with a confirmed objective response was 26% (95% confidence interval [CI], 17 to 38) and the percentage of participants with disease control was 85% (95% CI, 74 to 92). The median duration of response was 20.4 months (95% CI, 8.3 to not reached), with a median duration of progression-free survival of 22.3 months (95% CI, 13.8 to not reached). Overall survival was 76% at 24 months. Among the 60 participants who were receiving antihypertensive medications, 19 (32%) had a reduction of at least 50% in the total daily dose of at least one antihypertensive medication for at least 6 months after starting treatment with belzutifan. Treatment-related adverse events occurred in 71 participants (99%); anemia of grade 3 was noted in 22% of the participants. Eight participants (11%) had treatment-related serious adverse events.ConclusionsBelzutifan showed antitumor activity with durable responses in participants with advanced pheochromocytoma or paraganglioma. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-015 ClinicalTrials.gov number, NCT04924075.)

Frailty is acommon geriatric syndrome in older patients with cancer. It affects prognosis and treatment tolerance in various ways. Frailty and cancer share several common risk factors, which are reflected in the hallmarks of aging. An oncogeriatric assessment with management (GAME) provides the opportunity to detect frailty and its related geriatric impairments and offers the possibility to compensate for frailty-associated vulnerability. Thus, higher-grade treatment-associated toxicities of the provided oncological treatments are reduced. Furthermore, treatment completion rates and quality of life can be improved by GAME. The following review article provides an overview of the general definition of physical and social frailty, its significance in oncology, and the evidence for GAME. Lastly, first study results of frailty-adapted treatment approaches are summarized.

Abstract Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2α (HIF2α) mRNA, which increases renal erythropoietin production. Here we show that Irp1 -/- mice develop fasting hypoglycemia and are protected against high-fat diet–induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1 -/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.