FANCM promotes PARP inhibitor resistance by minimizing ssDNA gap formation and counteracting resection inhibition.

Poly(ADP-ribose) polymerase inhibitors (PARPis) exhibit remarkable anticancer activity in tumors with homologous recombination (HR) gene mutations. However, the role of other DNA repair proteins in PARPi-induced lethality remains elusive. Here, we reveal that FANCM promotes PARPi resistance independent of the core Fanconi anemia (FA) complex. FANCM-depleted cells retain HR proficiency, acting independently of BRCA1 in response to PARPis. FANCM depletion leads to increased DNA damage in the second S phase after PARPi exposure, driven by elevated single-strand DNA (ssDNA) gap formation behind replication forks in the first S phase. These gaps arise from both 53BP1- and primase and DNA directed polymerase (PRIMPOL)-dependent mechanisms. Notably, FANCM-depleted cells also exhibit reduced resection of collapsed forks, while 53BP1 deletion restores resection and mitigates PARPi sensitivity. Our results suggest that FANCM counteracts 53BP1 to repair PARPi-induced DNA damage. Furthermore, FANCM depletion leads to increased chromatin bridges and micronuclei formation after PARPi treatment, elucidating the mechanism underlying extensive cell death in FANCM-depleted cells.

Pericyte derivation and transplantation for blood-CNS barrier reconstitution in CNS disorders.

Disruption of the blood-central nervous system barrier (BCB) is increasingly recognized as a pathological factor in diseases and trauma of the central nervous system. Despite the neuropathological impact, current treatment modalities do not target the BCB; strategies to reconstitute the impaired BCB have been restricted to nutritional and dietary remedies. As an integral cell type in the neurovascular unit, pericytes are crucial to the development, maintenance, and repair of the BCB. As such, pericytes are well poised as cellular agents for reconstitution of the impaired BCB. Here, we summarize recent revelations regarding the role of BCB disruption in diseases and trauma of the central nervous system and highlight how pericytes are harnessed to provide targeted therapeutic effect in each case. This review will also address how recent advances in pericyte derivation strategies can serve to overcome practical hurdles in the clinical use of pericytes.

Magnon interactions in a moderately correlated Mott insulator.

Quantum fluctuations in low-dimensional systems and near quantum phase transitions have significant influences on material properties. Yet, it is difficult to experimentally gauge the strength and importance of quantum fluctuations. Here we provide a resonant inelastic x-ray scattering study of magnon excitations in Mott insulating cuprates. From the thin film of SrCuO2, single- and bi-magnon dispersions are derived. Using an effective Heisenberg Hamiltonian generated from the Hubbard model, we show that the single-magnon dispersion is only described satisfactorily when including significant quantum corrections stemming from magnon-magnon interactions. Comparative results on La2CuO4 indicate that quantum fluctuations are much stronger in SrCuO2 suggesting closer proximity to a magnetic quantum critical point. Monte Carlo calculations reveal that other magnetic orders may compete with the antiferromagnetic Néel order as the ground state. Our results indicate that SrCuO2-due to strong quantum fluctuations-is a unique starting point for the exploration of novel magnetic ground states.

Differential involvement of cAMP/PKA-, PLC/PKC- and Ca2+/calmodulin-dependent pathways in GnRH-induced prolactin secretion and gene expression in grass carp pituitary cells.

Gonadotropin-releasing hormone (GnRH) is a key stimulator for gonadotropin secretion in the pituitary and its pivotal role in reproduction is well conserved in vertebrates. In fish models, GnRH can also induce prolactin (PRL) release, but little is known for the corresponding effect on PRL gene expression as well as the post-receptor signalling involved. Using grass carp as a model, the functional role of GnRH and its underlying signal transduction for PRL regulation were examined at the pituitary level. Using laser capture microdissection coupled with RT-PCR, GnRH receptor expression could be located in carp lactotrophs. In primary cell culture prepared from grass carp pituitaries, the native forms of GnRH, GnRH2 and GnRH3, as well as the GnRH agonist [D-Arg6, Pro9, NEt]-sGnRH were all effective in elevating PRL secretion, PRL mRNA level, PRL cell content and total production. In pituitary cells prepared from the rostral pars distalis, the region in the carp pituitary enriched with lactotrophs, GnRH not only increased cAMP synthesis with parallel CREB phosphorylation and nuclear translocation but also induced a rapid rise in cytosolic Ca2+ by Ca2+ influx via L-type voltage-sensitive Ca2+ channel (VSCC) with subsequent CaM expression and NFAT2 dephosphorylation. In carp pituitary cells prepared from whole pituitaries, GnRH-induced PRL secretion was reduced/negated by inhibiting cAMP/PKA, PLC/PKC and Ca2+/CaM/CaMK-II pathways but not the signalling events via IP3 and CaN/NFAT. The corresponding effect on PRL mRNA expression, however, was blocked by inhibiting cAMP/PKA/CREB/CBP and Ca2+/CaM/CaN/NFAT2 signalling but not PLC/IP3/PKC pathway. At the pituitary cell level, activation of cAMP/PKA pathway could also induce CaM expression and Ca2+ influx via VSCC with parallel rises in PRL release and gene expression in a Ca2+/CaM-dependent manner. These findings, as a whole, suggest that the cAMP/PKA-, PLC/PKC- and Ca2+/CaM-dependent cascades are differentially involved in GnRH-induced PRL secretion and PRL transcript expression in carp lactotrophs. During the process, a functional crosstalk between the cAMP/PKA- and Ca2+/CaM-dependent pathways may occur with PRL release linked with CaMK-II and PKC activation and PRL gene transcription caused by nuclear action of CREB/CBP and CaN/NFAT2 signalling.

Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration.

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)-expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

Phase Transition Control in Molecular Solids via Complementarity of Hydrogen-Bond Strength.

Phase transitions in molecular solids involve synergistic changes in chemical and electronic structures, leading to diversification in physical and chemical properties. Despite the pivotal role of hydrogen bonds (H-bonds) in many phase-transition materials, it is rare and challenging to chemically regulate the dynamics and to elucidate the structure-property relationship. Here, four high-spin CoII compounds were isolated and systematically investigated by modifying the ligand terminal groups (X=S, Se) and substituents (Y=Cl, Br). S-Cl and Se-Br undergo a reversible structural phase transition near room temperature, triggering the rotation of 15-crown-5 guests and the swing between syn- and anti-conformation of NCX- ligands, accompanied by switchable magnetism. Conversely, S-Br and Se-Cl retain stability in ordered and disordered phases, respectively. H-bonds geometric analysis and ab initio calculations reveal that the electronegativity of X and Y affects the strength of NY-ap-H⋅⋅⋅X interactions. Entropy-driven structural phase transitions occur when the H-bond strength is appropriate; otherwise, the phase stays unchanged if it is too strong or weak. This work highlights a phase transition driven by H-bond strength complementarity - pairing strong acceptor with weak donor and vice versa, which offers a straightforward and effective approach for designing phase-transition molecular solids from a chemical perspective.

Rare-variant association study unveils the Achilles' heel for HCC.

In this issue of Cell Genomics, Wang, Liu, Zuo, Wang, et al.1 investigate rare variants in hepatocellular carcinoma (HCC) by performing the first rare-variant association study (RVAS) in a Chinese population cohort. It uncovers BRCAness phenotypes associated with the NRDE2-p.N377I variant, suggesting PARP inhibitors as a promising therapeutic approach for certain HCC patients.

Hidden non-collinear spin-order induced topological surface states.

Rare-earth monopnictides are a family of materials simultaneously displaying complex magnetism, strong electronic correlation, and topological band structure. The recently discovered emergent arc-like surface states in these materials have been attributed to the multi-wave-vector antiferromagnetic order, yet the direct experimental evidence has been elusive. Here we report observation of non-collinear antiferromagnetic order with multiple modulations using spin-polarized scanning tunneling microscopy. Moreover, we discover a hidden spin-rotation transition of single-to-multiple modulations 2 K below the Néel temperature. The hidden transition coincides with the onset of the surface states splitting observed by our angle-resolved photoemission spectroscopy measurements. Single modulation gives rise to a band inversion with induced topological surface states in a local momentum region while the full Brillouin zone carries trivial topological indices, and multiple modulation further splits the surface bands via non-collinear spin tilting, as revealed by our calculations. The direct evidence of the non-collinear spin order in NdSb not only clarifies the mechanism of the emergent topological surface states, but also opens up a new paradigm of control and manipulation of band topology with magnetism.

A 1-year longitudinal study on experiencing workplace cyberbullying, affective well-being and work engagement of teachers: The mediating effect of cognitive reappraisal.

Research on experiencing workplace cyberbullying (WCB) and its underlying mechanisms that impact the well-being of teachers is scarce. We propose that cognitive reappraisal, which is a useful and adaptive emotion-regulation strategy for reinterpreting emotion-eliciting situations, is a mediator explaining the inverse relationships between experiencing WCB and well-being. A three-wave longitudinal survey (baseline, T1; 3 months, T2; and 1 year, T3) was conducted with a sample of 444 primary and secondary schoolteachers in Hong Kong, China. Exposure to WCB, cognitive reappraisal, affective well-being and work engagement of participants was assessed. In line with the hypotheses, results showed that cognitive reappraisal mediated the associations between WCB and well-being. WCB at T1 was negatively associated with cognitive reappraisal at T2, which in turn was positively associated with positive affect and work engagement and negatively associated with negative affect at T3. Findings suggest that the intrusive nature of WCB renders its victims emotionally exhausted and helpless, thus negatively impacting the process to reinterpret the situation in a positive light, resulting in undesirable consequences. This study has illuminated WCB's inhibitory mechanism and its long-term detrimental impact. Practical implications are discussed.

Neonatal GABAergic transmission primes vestibular gating of output for adult spatial navigation.

GABAergic interneurons are poised with the capacity to shape circuit output via inhibitory gating. How early in the development of medial vestibular nucleus (MVN) are GABAergic neurons recruited for feedforward shaping of outputs to higher centers for spatial navigation? The role of early GABAergic transmission in assembling vestibular circuits for spatial navigation was explored by neonatal perturbation. Immunohistochemistry and confocal imaging were utilized to reveal the expression of parvalbumin (PV)-expressing MVN neurons and their perineuronal nets. Whole-cell patch-clamp recording, coupled with optogenetics, was conducted in vitro to examine the synaptic function of MVN circuitry. Chemogenetic targeting strategy was also employed in vivo to manipulate neuronal activity during navigational tests. We found in rats a neonatal critical period before postnatal day (P) 8 in which competitive antagonization of GABAergic transmission in the MVN retarded maturation of inhibitory neurotransmission, as evidenced by deranged developmental trajectory for excitation/inhibition ratio and an extended period of critical period-like plasticity in GABAergic transmission. Despite increased number of PV-expressing GABAergic interneurons in the MVN, optogenetic-coupled patch-clamp recording indicated null-recruitment of these neurons in tuning outputs along the ascending vestibular pathway. Such perturbation not only offset output dynamics of ascending MVN output neurons, but was further accompanied by impaired vestibular-dependent navigation in adulthood. The same perturbations were however non-consequential when applied after P8. Results highlight neonatal GABAergic transmission as key to establishing feedforward output dynamics to higher brain centers for spatial cognition and navigation.

Intrinsic and extrinsic actions of human neural progenitors with SUFU inhibition promote tissue repair and functional recovery from severe spinal cord injury.

Neural progenitor cells (NPCs) derived from human pluripotent stem cells(hPSCs) provide major cell sources for repairing damaged neural circuitry and enabling axonal regeneration after spinal cord injury (SCI). However, the injury niche and inadequate intrinsic factors in the adult spinal cord restrict the therapeutic potential of transplanted NPCs. The Sonic Hedgehog protein (Shh) has crucial roles in neurodevelopment by promoting the formation of motorneurons and oligodendrocytes as well as its recently described neuroprotective features in response to the injury, indicating its essential role in neural homeostasis and tissue repair. In this study, we demonstrate that elevated SHH signaling in hNPCs by inhibiting its negative regulator, SUFU, enhanced cell survival and promoted robust neuronal differentiation with extensive axonal outgrowth, counteracting the harmful effects of the injured niche. Importantly, SUFU inhibition in NPCs exert non-cell autonomous effects on promoting survival and neurogenesis of endogenous cells and modulating the microenvironment by reducing suppressive barriers around lesion sites. The combined beneficial effects of SUFU inhibition in hNPCs resulted in the effective reconstruction of neuronal connectivity with the host and corticospinal regeneration, significantly improving neurobehavioral recovery in recipient animals. These results demonstrate that SUFU inhibition confers hNPCs with potent therapeutic potential to overcome extrinsic and intrinsic barriers in transplantation treatments for SCI.

Interface-induced superconductivity in magnetic topological insulators.

The interface between two different materials can show unexpected quantum phenomena. In this study, we used molecular beam epitaxy to synthesize heterostructures formed by stacking together two magnetic materials, a ferromagnetic topological insulator (TI) and an antiferromagnetic iron chalcogenide (FeTe). We observed emergent interface-induced superconductivity in these heterostructures and demonstrated the co-occurrence of superconductivity, ferromagnetism, and topological band structure in the magnetic TI layer-the three essential ingredients of chiral topological superconductivity (TSC). The unusual coexistence of ferromagnetism and superconductivity is accompanied by a high upper critical magnetic field that exceeds the Pauli paramagnetic limit for conventional superconductors at low temperatures. These magnetic TI/FeTe heterostructures with robust superconductivity and atomically sharp interfaces provide an ideal wafer-scale platform for the exploration of chiral TSC and Majorana physics.

Ginsenoside Rg1 promotes fetal hemoglobin production in vitro: A potential therapeutic avenue for ß-thalassemia.

ß-thalassemia, a globally prevalent genetic disorder, urgently requires innovative treatment options. Fetal hemoglobin (HbF) induction stands as a key therapeutic approach. This investigation focused on Ginsenoside Rg1 from the Panax genus for HbF induction. Employing K562 cells and human erythroid precursor cells (ErPCs) derived from neonatal cord blood, the study tested Rg1 at different concentrations. We measured its effects on γ-globin mRNA levels and HbF expression, alongside assessments of cell proliferation and differentiation. In K562 cells, Rg1 at 400 µM significantly increased γ-globin mRNA expression by 4.24 ± 1.08-fold compared to the control. In ErPCs, the 800 µM concentration was most effective, leading to an over 80% increase in F-cells and a marked upregulation in HbF expression. Notably, Rg1 did not adversely affect cell proliferation or differentiation, with the 200 µM concentration showing an increase in γ-globin mRNA by 2.33 ± 0.58-fold, and the 800 µM concentration enhancing HbF expression by 2.59 ± 0.03-fold in K562 cells. Our results underscore Rg1's potential as an effective and safer alternative for ß-thalassemia treatment. By significantly enhancing HbF levels without cytotoxicity, Rg1 offers a notable advantage over traditional treatments like Hydroxyurea. While promising, these in vitro findings warrant further in vivo exploration to confirm Rg1's therapeutic efficacy and to unravel its underlying mechanistic pathways.

Unraveling the role of vaporization momentum in self-jumping dynamics of freezing supercooled droplets at reduced pressures.

Supercooling of water complicates phase change dynamics, the understanding of which remains limited yet vital to energy-related and aerospace processes. Here, we investigate the freezing and jumping dynamics of supercooled water droplets on superhydrophobic surfaces, induced by a remarkable vaporization momentum, in a low-pressure environment. The vaporization momentum arises from the vaporization at droplet's free surface, progressed and intensified by recalescence, subsequently inducing droplet compression and finally self-jumping. By incorporating liquid-gas-solid phase changes involving vaporization, freezing recalescence, and liquid-solid interactions, we resolve the vaporization momentum and droplet dynamics, revealing a size-scaled jumping velocity and a nucleation-governed jumping direction. A droplet-size-defined regime map is established, distinguishing the vaporization-momentum-dominated self-jumping from evaporative drying and overpressure-initiated levitation, all induced by depressurization and vaporization. Our findings illuminate the role of supercooling and low-pressure mediated phase change in shaping fluid transport dynamics, with implications for passive anti-icing, advanced cooling, and climate physics.

Chromatin bridges: stochastic breakage or regulated resolution?

Genetic material is organized in the form of chromosomes, which need to be segregated accurately into two daughter cells in each cell cycle. However, chromosome fusion or the presence of unresolved interchromosomal linkages lead to the formation of chromatin bridges, which can induce DNA lesions and genome instability. Persistent chromatin bridges are trapped in the cleavage furrow and are broken at or after abscission, the final step of cytokinesis. In this review, we focus on recent progress in understanding the mechanism of bridge breakage and resolution. We discuss the molecular machinery and enzymes that have been implicated in the breakage and processing of bridge DNA. In addition, we outline both the immediate outcomes and genomic consequences induced by bridge breakage.

Site fidelity of migratory shorebirds facing habitat deterioration: insights from satellite tracking and mark-resighting.

BACKGROUND: Site fidelity, the tendency to return to a previously visited site, is commonly observed in migratory birds. This behaviour would be advantageous if birds returning to the same site, benefit from their previous knowledge about local resources. However, when habitat quality declines at a site over time, birds with lower site fidelity might benefit from a tendency to move to sites with better habitats. As a first step towards understanding the influence of site fidelity on how animals cope with habitat deterioration, here we describe site fidelity variation in two species of sympatric migratory shorebirds (Bar-tailed Godwits Limosa lapponica and Great Knots Calidris tenuirostris). Both species are being impacted by the rapid loss and deterioration of intertidal habitats in the Yellow Sea where they fuel up during their annual long-distance migrations. METHODS: Using satellite tracking and mark-resighting data, we measured site fidelity in the non-breeding (austral summer) and migration periods, during which both species live and co-occur in Northwest Australia and the Yellow Sea, respectively. RESULTS: Site fidelity was generally high in both species, with the majority of individuals using only one site during the non-breeding season and revisiting the same sites during migration. Nevertheless, Great Knots did exhibit lower site fidelity than Bar-tailed Godwits in both Northwest Australia and the Yellow Sea across data types. CONCLUSIONS: Great Knots encountered substantial habitat deterioration just before and during our study period but show the same rate of decline in population size and individual survival as the less habitat-impacted Bar-tailed Godwits. This suggests that the lower site fidelity of Great Knots might have helped them to cope with the habitat changes. Future studies on movement patterns and their consequences under different environmental conditions by individuals with different degrees of site fidelity could help broaden our understanding of how species might react to, and recover from, local habitat deterioration.

Goldfish adiponectin: (I) molecular cloning, tissue distribution, recombinant protein expression, and novel function as a satiety factor in fish model.

Adiponectin (AdipoQ) is an adipokine involved in glucose homeostasis and lipid metabolism. In mammals, its role in appetite control is highly controversial. To shed light on the comparative aspects of AdipoQ in lower vertebrates, goldfish was used as a model to study feeding regulation by AdipoQ in fish species. As a first step, goldfish AdipoQ was cloned and found to be ubiquitously expressed at the tissue level. Using sequence alignment, protein modeling, phylogenetic analysis and comparative synteny, goldfish AdipoQ was shown to be evolutionarily related to its fish counterparts and structurally comparable with AdipoQ in higher vertebrates. In our study, recombinant goldfish AdipoQ was expressed in E. coli, purified by IMAC, and confirmed to be bioactive via activation of AdipoQ receptors expressed in HepG2 cells. Feeding in goldfish revealed that plasma levels of AdipoQ and its transcript expression in the liver and brain areas involved in appetite control including the telencephalon, optic tectum, and hypothalamus could be elevated by food intake. In parallel studies, IP and ICV injection of recombinant goldfish AdipoQ in goldfish was effective in reducing foraging behaviors and food consumption. Meanwhile, transcript expression of orexigenic factors (NPY, AgRP, orexin, and apelin) was suppressed with parallel rises in anorexigenic factors (POMC, CART, CCK, and MCH) in the telencephalon, optic tectum and/or hypothalamus. In these brain areas, transcript signals for leptin receptor were upregulated with concurrent drops in the NPY receptor and ghrelin receptors. In the experiment with IP injection of AdipoQ, transcript expression of leptin was also elevated with a parallel drop in ghrelin mRNA in the liver. These findings suggest that AdipoQ can act as a novel satiety factor in goldfish. In this case, AdipoQ signals (both central and peripheral) can be induced by feeding and act within the brain to inhibit feeding behaviors and food intake via differential regulation of orexigenic/anorexigenic factors and their receptors. The feeding inhibition observed may also involve the hepatic action of AdipoQ by modulation of feeding regulators expressed in the liver.

Evaluation of the deficiency status of 25-hydroxyvitamin D and associated factors in Southwest China: A hospital-based retrospective cross-sectional analysis of a low-latitude, high-altitude, multiracial region.

Vitamin D deficiency is widespread in different populations and regions worldwide and has become a global health issue. The vitamin D status of the population in the Yunnan Province of Southwest China has not been evaluated to date. Therefore, in this study, we evaluated the vitamin D status according to the serum concentrations of 25-hydroxyvitamin D (25(OH)D) in individuals of Yunnan Province, a low-latitude, high-altitude and multiracial region in China. The data on 25(OH)D concentrations from October 2012 to December 2017 were retrospectively collected and assessed using the laboratory information system from 52 950 hospital-based participants (age, 1 day-96 years; females, 73.74%). The serum concentration of 25(OH)D was evaluated using a chemiluminescent immunoassay. The analysis was stratified by sex, age, sampling season, testing year, minority, residential district, latitude, altitude and meteorological factors. Vitamin D status was classified as follows: severe deficiency: <10 ng/mL; deficiency: <20 ng/mL; insufficiency: <30 ng/mL; and sufficiency: ≥30 ng/mL. The results showed that vitamin D deficiency is highly prevalent in Yunnan Province in a hospital-based cohort, with a deficiency and severe deficiency rate of 65.1% and a sufficiency rate of 5.30%. Significantly lower vitamin D levels and sufficiency rates were observed in females than in males (20.13 ± 7.22 ng/mL vs. 17.56 ± 6.66 ng/mL and 8.20% vs. 4.20%; p < 0.01, respectively); in spring and winter (16.93 ± 6.24 ng/mL; 2.97% and 16.38 ± 6.43 ng/mL; 3.06%, respectively) than in summer and autumn (20.23 ± 7.14 ng/mL; 8.02% and 19.10 ± 6.97 ng/mL; 6.61% [p < 0.01], respectively); and in older individuals (0-6 years: 28.29 ± 13.13 ng/mL vs. >60 years: 14.88 ± 8.39 ng/mL; p < 0.01). Relatively higher vitamin D levels were observed in individuals of Yi, Zhuang, Hani, Dai, Miao and Lisu minorities and lower levels in individuals of Hui and Zang minorities compared with those of the Han nationality (p < 0.01). The mean sunlight duration, mean air temperature, maximum ultraviolet value and latitude were significantly correlated with vitamin D levels (r = -0.53, 0.60, 0.31, -0.68, respectively; p < 0.05). These results suggest that vitamin D status is influenced by sex, age, minority, latitude and some meteorological factors in areas with high and low altitudes. Hence, new public health policies, such as advice on sunshine exposure, food fortification and nutrition education, as well as the implementation of vitamin D supplementation programmes must be considered to alleviate vitamin D deficiency in Yunnan province, Southwest China.

Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration.

Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M-deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration.