The retinal pigment epithelium (RPE) plays a pivotal role in retinal homeostasis and energy metabolism. A recent study demonstrates that RPE cells release insulin in response to photoreceptor outer segment (POS) phagocytosis and starvation conditions. However, the downstream signalling pathway of this local insulin production has not yet been identified. Therefore, using the ARPE-19 cell line as an in vitro model of human RPE, we have investigated insulin signalling in basal conditions and after rod OS phagocytosis. Our data show that ARPE-19 cells express key pancreatic β-cell markers, including the transcription factor Pancreatic and Duodenal Homeobox-1 (PDX-1), which translocates to the nucleus in response to phagocytosis, and prohormone convertase 1/3 (PC1/3). In addition, ARPE-19 cells synthesize and secrete insulin already in basal conditions, increasing their release after phagocytosis. The RPE-secreted insulin acts in an autocrine manner, activating the canonical insulin signalling pathway and leading to increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and AKT. An upregulation of the insulin-responsive glucose transporter GLUT4 and increased glucose uptake was also observed, fueling the ARPE-19 cells’ oxidative energy metabolism, incrementing the oxidative phosphorylation activity, probably to sustain the high energy demand associated with phagocytosis. At the same time, a decrease in lactate release has been observed. These features may have important implications for understanding retinal energy metabolism and developing novel therapeutic strategies for retinal neurodegenerative diseases.

Antioxidant capacity is a major determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) and radiotherapy (RT). Endoplasmic reticulum (ER) glucose-6-phosphate (G6P) metabolism, regulated by hexose-6-phosphate dehydrogenase (H6PD) and glucose-6-phosphatase 3 (G6PC3), sustains ER-linked nicotinamide adenine dinucleotide phosphate (NADPH) production and thereby supports glutathione (GSH)-dependent redox buffering; however, its clinical relevance and therapeutic exploitability in GBM remain poorly defined. Public GBM transcriptomic datasets were analyzed to assess the prognostic relevance of H6PD and G6PC3 expression. U87 GBM cells were treated with TMZ and fractionated RT, with or without transient chlorogenic acid (CGA) exposure administered prior to irradiation. CGA was selected as a modulator of ER G6P metabolism due to its capability to inhibit G6P transport across the reticular membrane. Cell survival, oxidative stress, intracellular redox balance, and metabolic activity were evaluated. High expression of H6PD and G6PC3 predicted poorer patient survival, with H6PD retaining independent prognostic significance, identifying ER-associated G6P/NADPH metabolism as an adverse metabolic signature in GBM. Transient CGA exposure significantly potentiated TMZ + RT cytotoxicity, increasing membrane damage and reducing cell survival after irradiation. CGA induced an early increase in oxidative stress followed by delayed depletion of reduced NADPH and GSH, amplifying redox imbalance under combinedchemoradiotherapy. Metabolic analyses indicated enhanced glycolytic engagement without further stimulation of mitochondrial respiration. ER-associated NADPH metabolism represents a clinically relevant determinant of redox resilience in GBM, with H6PD emerging as an independent prognostic marker within this metabolic axis. In a U87 proof-of-concept model, transient, timing-based metabolic priming with CGA disrupts antioxidant buffering and amplifies oxidative vulnerability during chemoradiotherapy, thereby enhancing tumor in vitro. These findings provide a strong mechanistic and translational rationale for targeting ER-linked redox metabolism as an adjuvant strategy to improve GBM responsiveness to standard chemoradiotherapy.

Prognosis for pediatric sarcoma (pSC)-affected patients, especially those with relapsed/refractory disease, is dismal. The available treatment options are unsatisfactory, challenging researchers to address this unmet need. The investigational B7-H3 targeted ADC vobramitamab duocarmazine (vobra duo) showed clinical effectiveness towards several B7-H3-positive adult tumors and pre-clinical efficacy in pediatric neuroblastoma models. Cytotoxicity of vobra duo was evaluated in 2D and 3D models toward pSC cell lines expressing B7-H3, showing a dose-dependent cell viability reduction. Proliferation was assessed by time-lapse single-cell segmentation. Compared to controls, vobra duo resulted in a significant increase in the cell doubling time. AKT/mTOR master effectors of cell proliferation were investigated by phospho-specific western blot assays. A down-modulation of phospho-AKT/ -P70 S6K and -4E-BP1 protein expression was detected in both A204 (rhabdomyosarcoma) and U-2-OS (osteosarcoma) cells, the most treatment-sensitive and resistant cell lines, respectively, suggesting their involvement in vobra duo-mediated anti-proliferative effect. In response to treatment, all cell lines underwent apoptotic cell death. A significant increase in the executioner cleaved caspase-3 was detected, and a partial but significant reversion of apoptotic cell death was noted following pre-treatment with the pan-caspase inhibitor, Q-VD-OP-h. Vobra duo also triggered caspase-independent apoptotic events: i) increased AIF nuclear translocation, ii) increased mitochondrial superoxide production, and iii) the depolarization of mitochondrial membrane potential. In vivo, the effectiveness of vobra duo was assayed by single and repeated intravenous administration in the mouse rhabdomyosarcoma model. The single injection of 3 mg/Kg of vobra duo induced a significant tumor growth delay. Repeated vobra duo doses ameliorated this outcome, reverting rhabdomyosarcorma to rhabdomyoma tumor, by increasing Desmin and Myogenin/Myf-4 differentiation markers expression, and reducing both Ki-67 and CD133. In conclusion, the in vitro and in vivo anti-tumor effects towards pSC highlight the need to extend the investigation to patient-derived preclinical models, to pave the way for clinical translation.

Lactate is recognized as a crucial signalling molecule within the tumor microenvironment, where it shapes immune responses by modulating various cell populations, including T cells and macrophages. However, its effect on natural killer (NK) cells, key effectors of early antitumor immunity, remains poorly understood. This study investigates how intratumoral lactate accumulation affects NK cell function in breast cancer, a neoplasm characterized by elevated glycolytic flux. An in-silico analysis of 882 breast cancer patients revealed that high lactate metabolism is inversely correlated with NK cell activation genes and is associated with poor prognosis. To corroborate these findings, NK cells from healthy donors were cultured under lactate-rich or control conditions. Lactate exposure impaired NK cell proliferation, downregulated activation markers and cytotoxic molecules, disrupted mitochondrial bioenergetics, and induced lipid accumulation, as demonstrated by flow cytometry, metabolic profiling, and Raman spectroscopy. Functional assays using microfluidic devices and degranulation tests revealed that lactate-exposed NK cells exhibited reduced chemotaxis and diminished cytotoxicity against MCF-7 and MDA-MB-231 breast cancer spheroids, accompanied by decreased CXCL9 and CXCL10 production. Pharmacologic inhibition of lactate transport, via Syrosingopine or MSC-4381 and AZD3965 combination, restored NK cell cytotoxicity in tumor co-cultures, as shown by increased NK cell degranulation, caspase-3/7-mediated tumor apoptosis, and spheroid shrinkage. Finally, GPR81 deletion mirrored these effects, enhancing NK cell activity. These findings identify lactate as a driver of NK cell suppression and highlight lactate transport and receptor targeting as a strategy to enhance NK cell-based immunotherapies in breast cancer and other lactate-rich tumors.

Osteoarthritis is a multifactorial chronic joint disease characterized by progressive cartilage degradation and inflammation. Since there is no effective cure, emerging therapeutic approaches, such as mesenchymal stromal cells (MSCs) transplantation, are currently under investigation. However, the clinical translation of MSC-based therapies is hampered by several limitations, such as donor-dependent variability and heterogeneity related to tissue sources. To address these issues, MSCs derived from induced pluripotent stem cells (iMSCs) have been proposed as a more standardized and scalable alternative. Due to the risks of cell-based therapy, extracellular vesicles (EVs), particularly iMSC-EVs (iEVs), could represent a promising cell-free approach for OA treatment. The present study aimed at characterizing iMSC-derived EVs and evaluating their functional role in modulating inflammatory responses and redox balance in an in vitro OA model. Notably, recent evidence highlights the central role of EV-encapsulated microRNAs (EV-miRNAs) in mediating these effects. EVs isolated from iMSC conditioned media were characterized, and their miRNA content was analyzed at different culture passages. Selected miRNAs were subsequently assessed for their biological activity in an in vitro OA model, with a focus on their impact on inflammatory mediators and oxidative stress parameters. Specifically, six miRNAs such as hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p differentially reflect the anti-inflammatory and antioxidant effects of iMSCs-EVs treatment, suggesting possible synergistic effects. Their combined effect in the in vitro model confirmed their potential modulation in the expression of pro-inflammatory cytokines. Furthermore, their treatment markedly reduced ROS accumulation and oxidative damage, while restoring antioxidant defense systems. These findings support the therapeutic potential of iMSC-derived EVs as a cell-free strategy for OA treatment. The miRNA cargo encapsulated within iEVs appears to play a pivotal role in modulating inflammation and oxidative stress, emphasizing their promise as a novel, minimally invasive approach for disease modification in OA.

Fanconi anemia (FA) is a rare inherited disorder classically defined by defective DNA interstrand crosslink repair, leading to bone marrow failure and cancer predisposition. Increasing evidence indicates that FA pathophysiology extends beyond genomic instability to include mitochondrial dysfunction, oxidative stress, and impaired antioxidant responses. Across multiple cellular models and patient-derived samples, FA cells display altered mitochondrial bioenergetics, increased reactive oxygen species (ROS) production, and defective activation of redox-adaptive pathways, contributing to cumulative damage to DNA, lipids, and proteins. These alterations are particularly relevant in hematopoietic stem and progenitor cells, where metabolic stress and redox imbalance amplify stem cell exhaustion. Current data support a bidirectional interplay in which mitochondrial dysfunction and oxidative stress act mainly as secondary but amplifying factors of the primary DNA repair defect, establishing pathogenic feedback loops. Preclinical studies suggest that modulation of redox balance and mitochondrial function may improve cellular homeostasis, and early clinical investigations of antioxidant strategies indicate acceptable safety and measurable effects on oxidative biomarkers. However, clinical evidence remains limited and heterogeneous, with uncertain impact on long-term disease progression. Moreover, most mechanistic insights derive from in vitro or patient-derived models, while animal models and longitudinal clinical studies remain insufficient. Overall, a more integrated and translational framework is needed to clarify causality, validate biomarkers, and define the therapeutic potential of targeting metabolic and redox pathways in FA.

Fanconi anemia (FA) is a rare inherited bone marrow failure syndrome characterized by genomic instability, mitochondrial dysfunction, and oxidative stress. While the therapeutic potential of ataluren, a translational readthrough-inducing drug, has been investigated in FA cells carrying nonsense mutations, its broader metabolic impact remains unclear. Here, we demonstrate that ataluren (tested at 2.5, 5, and 10 μM) modulates cellular energy metabolism and redox homeostasis in FA lymphoblasts harboring either nonsense or missense mutations in the FANCA gene. At low doses (2.5 μM for 72 h), ataluren improved the ATP/AMP ratio, enhanced oxidative phosphorylation efficiency, and reduced lipid peroxidation and oxidative DNA damage. These effects were independent of mutation type and were not associated with compensatory glycolysis, as lactate dehydrogenase activity remained unchanged. Strikingly, ataluren restored the P/O ratio under pyruvate/malate-driven respiration to near-normal values, indicating improved coupling between oxygen consumption and ATP synthesis. Mechanistically, ataluren reduced DRP1 protein levels and attenuated mTOR-S6 signaling, suggesting that mitochondrial dynamics and bioenergetic efficiency are modulated via the mTOR–DRP1 axis. Additionally, ataluren lowered IMPDH activity, contributing to reduced cell proliferation and DNA damage without impairing cellular energy status. Notably, these beneficial effects persisted under immune stimulation, where ataluren mitigated the metabolic and oxidative burden imposed by lymphocyte activation. Our findings unveil a pleiotropic role for ataluren that extends beyond its canonical readthrough activity, highlighting its potential as a metabolic modulator for FA and possibly other DNA repair–deficient disorders.

The vertebrate retina is among the most energy-demanding tissues in the body, with photoreceptors accounting for most of its metabolic activity. The photoreceptor outer segment, devoid of mitochondria, carries out visual transduction. Oxidative phosphorylation in the rod inner segment has been considered the primary source of ATP in the photoreceptor; however, the bioenergetic requirements of the outer segment remain insufficiently explained. Models based on glycolysis, metabolite diffusion, and lactate shuttling do not fully account for the rapid energy demands of phototransduction and recovery in the outer segment. The rod requires local, timely metabolic support of opposite bioenergetic demands during the light/darkness cycle. In this review, we revisit the bioenergetics of rod outer segments by integrating historical biochemical data, proteomic and functional evidence, and new data suggesting the presence of oxidative metabolic processes within outer segment disks. We propose a compartmentalized metabolic structure in which inner segment mitochondria, aerobic glycolysis, and a putative ectopic oxidative phosphorylation system in the outer segment in a triple metabolic mechanism, to supply their localized and divergent ATP demands. We examine how this metabolic organization influences redox balance and how its disruption may explain their vulnerability in aging and disease. We also discuss the crosstalk between the outer segments and the retinal pigment epithelium, establishing a pro-oxidative condition in the outer retina as well as the effects of localized oxidative stress in many acquired retinal dystrophies. This perspective revisits the conventional view that oxidative phosphorylation in photoreceptors is restricted to inner segment mitochondria and highlights new directions for investigating retinal bioenergetics and pathophysiology.

This prospective study investigated the effects of photobiomodulation therapy (PBMT) at 810 nm on rescue in vitro maturation (rescue-IVM) of human immature oocytes following controlled ovarian stimulation (COS). A total of 260 immature oocytes (germinal vesicles (GV): 143; metaphase I (MI): 117) were collected from 114 women undergoing COS between December 2023 and July 2025, denuded, and randomized into control or PBMT groups; ten in vivo-matured MII oocytes served as references. PBMT was applied at 810 nm, 1.0 W, 60 J/cm2 for 1 min, and nuclear maturation and morphology were assessed up to 6 h of IVM. ATP content, mitochondrial oxidative phosphorylation (OxPhos) activity, and lipid peroxidation (MDA) were measured using luminometric, oximetric, and spectrophotometric assays. PBMT accelerated maturation, with GV and MI oocytes progressed to the next maturation stage 112.5% and 92.3% faster, respectively, within 1 h. ATP content increased markedly in PBMT-treated oocytes (P < 0.0001), with early-resuming MI oocytes exceeding levels of in vivo MII oocytes. OxPhos activity increased by 240% (GV) and 194% (MI) immediately after irradiation without mitochondrial uncoupling, while MDA levels remained stable. Collectively, these results demonstrated that PBMT accelerated cell cycle progression to GV and MI oocytes by enhancing mitochondrial OxPhos and ATP production without inducing oxidative stress. Limitations include the need for larger cohorts, evaluation of safety through assessment of potential DNA damage, and validation in poor-prognosis or advanced maternal age patients. This pioneering proof-of-concept study highlights the potential of PBMT to temporally accelerate rescue-IVM of immature oocytes - and possibly cumulus-oocyte complexes - in poor-responder patients undergoing IVF or fertility preservation.

Mutations in NOTCH1, which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as NOTCH1 wild-type (CLL/NWT) or mutated (CLL/NM), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/NM. These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate NOTCH1 mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/NWT) or mutated (MEC-1/NM) clones in a UM-BCR background. Here, NOTCH1 hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/NM cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/NWT. Importantly, CLL/NM cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in NOTCH1-mutated CLL. Representation of the molecular mechanism behind the metabolic reprogramming. BCR and NOTCH1 drive a dual metabolic reprogramming of glucose and glutamine pathways. In NOTCH1-mutated cells, both glucose and glutamine uptake are positively increased and even more upon BCR stimulation. Glucose is preferentially used to fuel the pentose phosphate pathway, and glutamine the TCA cycle. Concurrently, NICD accumulation, driven by BCR signaling, promotes TFAM expression and mitochondrial biogenesis. The resulting increase in mitochondrial mass underpins enhanced ATP production, oxygen consumption, and ROS generation, establishing a glutamine-dependent mitochondrial phenotype. This dependency sensitizes NOTCH1-mutated cells to glutamine blockade, which selectively induces apoptosis, further enhanced by combination with BCL-2 inhibition.

Abstract Elevated levels of the NAD+-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in multiple myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials because of the existence of alternative NAD+ production routes using NAD+ precursors other than nicotinamide. Here, by leveraging mathematical modeling approaches integrated with transcriptome data, we defined the specific NAD+ landscape of MM cells and established that the Preiss-Handler pathway for NAD+ biosynthesis, which uses nicotinic acid as a precursor, supports NAD+ synthesis in MM cells via its key enzyme nicotinate phosphoribosyltransferase (NAPRT). Accordingly, we found that NAPRT confers resistance to NAD+-depleting agents. Transcriptomic, metabolic, and bioenergetic profiling of NAPRT-knockout (KO) MM cells showed these to have weakened endogenous antioxidant defenses, increased propensity to oxidative stress, and enhanced genomic instability. Concomitant NAMPT inhibition further compounded the effects of NAPRT-KO, effectively sensitizing MM cells to the chemotherapeutic drug, melphalan; NAPRT added-back fully rescues these phenotypes. Overall, our results propose comprehensive NAD+ biosynthesis inhibition, through simultaneously targeting NAMPT and NAPRT, as a promising strategy to be tested in randomized clinical trials involving transplant-eligible patients with MM, especially those with more aggressive disease.

In Chronic Lymphocytic Leukemia (CLL), mutations at the TP53 tumor suppressor gene are an important hallmark since they may strongly influence the therapeutic decision. PRIMA-1Met (also known as APR-246/Eprenetapopt) is a small molecule able to restore the wild-type (wt) p53 conformation to mutant p53 proteins and to stimulate apoptosis in tumor cells; in addition, it can deplete the glutathione reservoir, increasing reactive oxygen species (ROS) production. In this study, we investigated whether combining PRIMA-1Met with Sulfasalazine (SAS), a SLC7A11/xCT inhibitor, reduces CLL cell viability by targeting mutant p53 and the glutathione pathway. The results demonstrated that, in CLL cells, PRIMA-1Met did not restore the wt functions in the mutant p53 proteins, but it strongly reduced the antioxidant defense and induced cell death. PRIMA-1Met and SAS combination synergistically reduced cell survival regardless of p53 status and further impaired antioxidant capacity, especially in mutant p53 cells, linking their cytotoxic effect to redox imbalance. Thus, the association of PRIMA-1Met with drugs targeting the antioxidant response could represent a valid strategy to kill CLL cells carrying either wt or mutant p53.

How does photobiomodulation therapy (PBM-t) with laser at 810 nm wavelength impact rescue in vitro maturation (r-IVM) of human immature oocytes? Laser irradiation improves cell cycle progression after r-IVM of germinal vesicles (GV) and metaphase I (MI) oocytes through increased mitochondrial metabolism without harmful oxidative stress. After controlled ovarian stimulation (COS) approximately 20% of retrieved oocytes are immature (GV or MI). Immature oocytes are usually discarded in in vitro fertilization (IVF) and fertility preservation programs. Classical IVM involves immature oocytes from unstimulated or minimally stimulated cycles, whereas r-IVM has been recently proposed after conventional COS. Mitochondrial dysfunction and ATP deficit were linked to suboptimal oocyte maturation. Stimulation of mitochondrial photoacceptors with low-level laser energy, known as PBM-t, was characterized in various in vitro and in vivo models. To date no reports have addressed the effects of PBM-t on human oocytes during r-IVM and the mechanisms involved. Immature oocytes (VG: 76, MI: 68) were collected after the COS of 72 women between December 2023 and January 2025. After follicle aspiration 36 hours post trigger of final oocyte maturation and cumulus-oocyte complexes (COC) incubation for 2 hours in G-IVFTM medium (Vitrolife) at 37 °C, 6% CO2, 5% O2, 89% N2, the oocytes were denuded. Immature oocytes were randomized into two groups: the control group and the test group which received laser treatment. Participants: women <40 years old, without ovulatory endocrine infertility, endometriosis, diminished ovarian reserve. PBM-t was performed at 810 nm with 1.0 W and fluence 60 J/cm2 for 1 minute (Garda-Laser). Oocyte nuclear maturation and morphology were assessed at 1-2-4-6 hours of IVM in G-1TM medium (Vitrolife). Oxidative phosphorylation (OxPhos), ATP and malondialdehyde concentration were evaluated by oximetric, luminometric and spectrophotometric analyses. Chi-square test was used for IVM rates, one-way ANOVA for metabolic analyses. The immature oocytes underwent r-IVM after PBM-t (33 VG from 27 patients, 35 MI from 24 patients) or without PBM-t (43 VG from 34 patients, 33 MI from 24 patients). No degeneration was observed in the PBM-t oocytes. The effect on cell cycle progression from VG to MI and from MI to MII was obtained 1 hour after irradiation and kept higher in the PBM-t group within 4 hours for VG and 6 hours for MI oocytes with respect to controls. The same behavior was observed in 44 sibling VG (23 after PBM-t and 21 controls) from 17 patients and 28 siblings MI (14 after PBM-t and 14 controls) from 10 patients. Biochemical data showed that ATP synthesis and oxygen consumption increased by approximately 180% immediately after irradiation, reaching a maximum of 240% after 10 minutes and remained unchanged even 1 hour after treatment. Despite increased mitochondrial energetic metabolism, no accumulation of malondialdehyde, a lipidic peroxidation marker, was detected since the OxPhos increment was not associated with an uncoupling between oxygen consumption and ATP synthesis. Intriguingly, the earlier VG and MI progress in the cell cycle, the significantly higher their ATP content (p < 0.01). Confirmation of these preliminary data on a wider sample cohort is mandatory and it is the main objective of our ongoing experiments along with the assessment of safety, i.e. the evaluation of the developmental potential of irradiated oocytes, and the quantification of mitochondrial DNA copy numbers changes during r-IVM. PBM-t improves cell cycle progression after r-IVM of VG and MI oocytes through increased energetic metabolism without oxidative stress. It may be a promising new tool to increase r-IVM of immature oocytes – and hopefully COC - in poor-responder patients undergoing IVF cycles or oocyte vitrification for fertility preservation. No

We used cryoEM to determine the structures of apo-NIS and NIS with I− and an oxyanion (ReO4−) bound to it (Fig. 1a) [1]. All apo- and holo-structures showed a NIS molecule in an occluded conformation, poised to open up toward the intracellular medium. The previous lack of information about other conformations NIS adopts in the course of its transport cycle, particularly its outwardly open conformation (Fig. 1b), severely limited our understanding of the NIS transport cycle. To fill this gap in our knowledge, we carried out molecular dynamics simulations of NIS under close-to-physiological conditions (Fig. 1c). The goal of our computational study was to explore the conformational space of NIS and gain insights into the conformations it assumes over the course of its transport cycle (Fig. 1d).

ANKRD26-related thrombocytopenia (ANKRD26-RT) is characterized by lifelong mild to moderate thrombocytopenia. Patients suffer from an increased susceptibility to acute or chronic myeloid leukemia, myelodysplastic syndrome, or chronic lymphocytic leukemia. We described here a patient with inherited thrombocytopenia initially misdiagnosed as immune thrombocytopenic purpura. A chromosomal deletion involving the ANKRD26 gene was identified. Gene and protein expression analyses suggest an alternative pathogenic mechanism of altered megakaryopoiesis: the synthesis of a chimeric protein with aberrant expression due to the unregulated action of a promoter from a gene located upstream of ANKRD26. This study highlights the importance of advanced genetic testing and functional analysis of patients’ primary cells in the case of the detection of previously unrecognized structural variants in order to understand pathogenic mechanisms. These investigations provided a definitive diagnosis for the patient and facilitated the development of a tailored clinical management strategy, especially concerning the potential for myeloid transformation.

Insulin is a key anabolic hormone traditionally considered to be exclusively produced by pancreatic β-cells. Insulin exerts several systemic effects involved in glucose uptake and metabolism. In the retina, insulin signaling acts as a regulator of photoreceptor- retinal pigment epithelium (RPE) metabolic coupling as well as of neuronal survival via the PI3K/Akt and MAPK/ERK pathways. Impaired insulin signaling contributes to diabetic retinopathy, retinitis pigmentosa, and age-related degeneration by disrupting energy homeostasis and trophic support. However, growing evidence suggests that the retina, particularly RPE, locally synthesizes and secretes insulin. Although the role of local insulin production in the retina remains to be clarified, this discovery introduces a paradigm shift in retinal physiology, suggesting a self-sustaining insulin signaling system that supports glucose uptake, lipid metabolism, and neurovascular integrity. Emerging data indicate that RPE-derived insulin is stimulated by photoreceptor outer segment (POS) phagocytosis and may act through autocrine and paracrine mechanisms to maintain retinal function, even under conditions of systemic insulin deficiency. Understanding this extra-pancreatic insulin source opens new therapeutic perspectives aimed at enhancing local insulin signaling to preserve vision and prevent retinal degeneration. Thus, the objective of this review is to summarize current evidence on RPE-derived insulin and to discuss its potential implications for retinal homeostasis and disease.