Synthetic vectors for activating the driving axis of ferroptosis.

Ferroptosis is a promising strategy for cancer therapy, with numerous inhibitors of its braking axes under investigation as potential drugs. However, few studies have explored the potential of activating the driving axes to induce ferroptosis. Herein, phosphatidylcholine peroxide decorating liposomes (LIPPCPO) are synthesized to induce ferroptosis by targeting divalent metal transporter 1 (DMT1). LIPPCPO is found to boost lysosomal Fe2+ efflux by inducing cysteinylation of lysosomal DMT1, resulting in glutathione peroxidase 4 (GPX4) suppression, glutathione depletion and ferroptosis in breast cancer cells and xenografts. Importantly, LIPPCPO induced ferroptotic cell death is independent of acquired resistance to radiation, chemotherapy, or targeted agents in 11 cancer cell lines. Furthermore, a strong synergistic ferroptosis effect is observed between LIPPCPO and an FDA-approved drug, artesunate, as well as X rays. The formula of LIPPCPO encapsulating artesunate significantly inhibits tumor growth and metastasis and improves the survival rate of breast cancer-bearing female mice. These findings provide a distinct strategy for inducing ferroptosis and highlight the potential of LIPPCPO as a vector to synergize the therapeutic effects of conventional ferroptosis inducers.

Stretch-induced hepatic endothelial mechanocrine promotes hepatocyte proliferation.

BACKGROUND AIMS: Partial hepatectomy (PHx)-induced liver regeneration causes the increase in relative blood flow rate within the liver, which dilates hepatic sinusoids and applies mechanical stretch on liver sinusoidal endothelial cells (LSECs). Heparin-binding EGF-like growth factor (HB-EGF) is a crucial growth factor during liver regeneration. We aimed to investigate whether this sinusoidal dilation-induced stretch promotes HB-EGF secretion in LSECs and what the related molecular mechanism is. APPROACH RESULTS: In vivo PHx, ex vivo liver perfusion and in vitro LSEC mechanical stretch were applied to detect HB-EGF expression in LSECs and hepatocyte proliferation. Knockdown or inhibition of mechanosensitive proteins were used to unravel the molecular mechanism in response to stretch. This stretch triggers amplitude- and duration-dependent HB-EGF up-regulation in LSECs, which is mediated by Yes-associated protein (YAP) nuclear translocation and binding to TEAD. This YAP translocation is achieved in two ways: On one hand, F-actin polymerization-mediated expansion of nuclear pores promotes YAP entry into nucleus passively. On the other hand, F-actin polymerization up-regulates the expression of BAG family molecular chaperone regulator 3 (BAG-3), which binds with YAP to enter nucleus cooperatively. In this process, ß1-integrin serves as a target mechanosensory in stretch-induced signaling pathways. This HB-EGF secretion-promoted liver regeneration after 2/3 PHx is attenuated in endothelial cell-specific Yap1-deficient mice. CONCLUSIONS: Our findings indicate that mechanical stretch-induced HB-EGF up-regulation in LSECs via YAP translocation can promote the hepatocyte proliferation during liver regeneration through a mechanocrine manner, which deepens the understanding of the mechanical-biological coupling in liver regeneration.

Lung megakaryocytes engulf inhaled airborne particles to promote intrapulmonary inflammation and extrapulmonary distribution.

Many lung immune cells are known to respond to inhaled particulate matter. However, current known responses cannot explain how particles induce thrombosis in the lung and how they translocate to distant organs. Here, we demonstrate that lung megakaryocytes (MKs) in the alveolar and interstitial regions display location-determined characteristics and act as crucial responders to inhaled particles. They move rapidly to engulf particles and become activated with upregulation in inflammatory responses and thrombopoiesis. Comprehensive in vivo, in vitro and ex vivo results unraveled that MKs were involved in particle-induced lung damages and shed particle-containing platelets into blood circulation. Moreover, MK-derived platelets exhibited faster clotting, stronger adhesion than normal resting platelets, and inherited the engulfed particles from parent MKs to assist in extrapulmonary particle transportation. Our findings collectively highlight that the specific responses of MKs towards inhaled particles and their roles in facilitating the translocation of particles from the lungs to extrapulmonary organs for clearance.

Overexpression of RBM4 promotes acute myeloid leukemia cell differentiation by regulating alternative splicing of TFEB.

Alternative splicing (AS) is an efficient and ubiquitous transcriptional regulatory mechanism that expands the coding capacity of the genome and is associated with the occurrence and progression of cancer. The differentiation-promoting regimen is a potential therapeutic approach in cancer treatment. In this study, we screened NPMc-positive and NPMc-negative AML samples from the Cancer Genome Atlas (TCGA), focusing on the splicing factor RBM4 and its splicing mechanism on the target gene TFEB, which are most relevant to the prognosis of AML. We also investigated the impact of the TFEB-dominant spliceosome on autophagy and differentiation of THP-1 and K562 cells. The results showed that RBM4 recognized the CU-rich sequence in intron 8 of TFEB, increasing the production of the TFEB-L spliceosome, which promoted autophagy. Overexpression of RBM4 increased autophagy and promoted cell differentiation. The combination of TFEB-L with the therapeutic drug rapamycin further promoted the differentiation of leukemia cell lines and primary leukemia cells in AML patients. This study suggested that overexpression of RBM4 could promote cell differentiation by promoting the production of the TFEB-dominant spliceosome, demonstrating the potential of the TFEB-dominant spliceosome combined with chemotherapy drugs to promote leukemia cell differentiation and improve patient prognosis.

Combining CD38 antibody with CD47 blockade is a promising strategy for treating hematologic malignancies expressing CD38.

Background: CD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs). Methods: Five suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 "mAb-trap" platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems. Results: Using hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a "mAb-trap" platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPα signal in CD38+/CD47+ tumor cells than IMM01 (SIRPα Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605-26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605-12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti-CD38 antibody 26B4 combined with the SIRPα-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605-12C10 efficiently eradicated all established tumors in all mice. Conclusion: A panel of BsAbs targeting CD38 and CD47 developed based on the "mAb-tarp" platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile.

Enhanced Intrusion of Exogenous Airborne Fine Particles toward Eyes in Humans and Animals: Where Damaged Blood-Ocular Barrier Plays a Crucial Role.

Emerging data suggest a close correlation between ambient fine particle (AFP) exposure and eye disorders and pinpoint potential threats of AFPs to eye health in humans. However, the possible passage (including direct intrusion) and the interactions of AFPs with the eye microenvironment in addition to morphological and physiological injuries remain elusive. To this end, the likely transport of AFPs into the eyes via blood-ocular barrier (BOB) in humans and animals was investigated herein. Exogenous particles were recognized inside human eyes with detailed structural and chemical fingerprints. Importantly, comparable AFPs were found in sera with constant structural and chemical fingerprints, hinting at the translocation pathway from blood circulation into the eye. Furthermore, we found that the particle concentrations in human eyes from patients with diabetic retinopathy were much higher than those from patients with no fundus pathological changes (i.e., myopia), indicating that the damaged BOB increased the possibility of particle entrance. Our diseased animal model further corroborated these findings. Collectively, our results offer a new piece of evidence on the intrusion of exogenous particles into human eyes and provide an explanation for AFP-induced eye disorders, with substantially increased risk in susceptible individuals with BOB injuries.

An overview for monitoring and prediction of pathogenic microorganisms in the atmosphere.

Corona virus disease 2019 (COVID-19) has exerted a profound adverse impact on human health. Studies have demonstrated that aerosol transmission is one of the major transmission routes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pathogenic microorganisms such as SARS-CoV-2 can survive in the air and cause widespread infection among people. Early monitoring of pathogenic microorganism transmission in the atmosphere and accurate epidemic prediction are the frontier guarantee for preventing large-scale epidemic outbreaks. Monitoring of pathogenic microorganisms in the air, especially in densely populated areas, may raise the possibility to detect viruses before people are widely infected and contain the epidemic at an earlier stage. The multi-scale coupled accurate epidemic prediction system can provide support for governments to analyze the epidemic situation, allocate health resources, and formulate epidemic response policies. This review first elaborates on the effects of the atmospheric environment on pathogenic microorganism transmission, which lays a theoretical foundation for the monitoring and prediction of epidemic development. Secondly, the monitoring technique development and the necessity of monitoring pathogenic microorganisms in the atmosphere are summarized and emphasized. Subsequently, this review introduces the major epidemic prediction methods and highlights the significance to realize a multi-scale coupled epidemic prediction system by strengthening the multidisciplinary cooperation of epidemiology, atmospheric sciences, environmental sciences, sociology, demography, etc. By summarizing the achievements and challenges in monitoring and prediction of pathogenic microorganism transmission in the atmosphere, this review proposes suggestions for epidemic response, namely, the establishment of an integrated monitoring and prediction platform for pathogenic microorganism transmission in the atmosphere.

Long- and Intermediate-Term Ambient Particulate Pollution Is Associated with Increased Osteoarthritis Risk: A Population-Based Prospective Analysis.

Recent studies found the intrusion and retention of exogenous fine particles into joints, but epidemiological data for long- and intermediate-term exposure associations are scare. Here, all urban working, retired employee, and rural residents (16.78 million) in Beijing from January 1, 2011 to December 31, 2019 were included to investigate the effects of long- and intermediate-term ambient particulate exposure on development of osteoarthritis. We identified 1,742,067 participants as first-visit patients with osteoarthritis. For each interquartile range increase in annual PM2.5 (23.32 µg/m3) and PM10 (23.92 µg/m3) exposure concentration, the pooled hazard ratios were respectively 1.238 (95% CI: 1.228, 1.249) and 1.178 (95% CI: 1.168, 1.189) for first osteoarthritis outpatient visits. Moreover, age at first osteoarthritis outpatient visits significantly decreased by 4.52 (95% CI: 3.45 to 5.40) days per µg/m3 for annual PM2.5 exposure at below 67.85 µg/m3. Finally, among the six constituents analyzed, black carbon appears to be the most important component associated with the association between PM2.5 exposure and the three osteoarthritis-related outcomes.

Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels.

Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.

Ligand Engineering for Mitigating Exciton-Phonon Coupling in Mixed Halide Perovskite Nanocrystals.

The vulnerability of mixed halide perovskite nanocrystals (NCs) remains challenging because of the weak interaction between commonly employed ligands, oleic acid/oleylamine (OAm/OA) and halide anions, coupled with substantial surface phonon energy. Here, we introduce 3-aminopropyltriethoxysilane (APTES) as a capping ligand to modify CsPbBrI2 NCs to enhance the interactions between them. The optical properties have been significantly enhanced, and halide segregation has been suppressed, both of which can be attributed to the reduced phonon energy and exciton-phonon coupling strength. Moreover, these APTES-CsPbBrI2 NCs exhibit a broad color gamut and sustained color stability during long-term operation, indicating their promising potential in display technologies. This work may offer insights into surface engineering to enhance the properties and band stability of mixed halide perovskite NCs.

Science-based evidence on pathways and effects of human exposure to micro- and nanoplastics.

Human exposure to plastic particles has raised great concern among all relevant stakeholders involved in the protection of human health due to the contamination of the food chain, surface waters, and even drinking water as well as due to their persistence and bioaccumulation. Now more than ever, it is critical that we understand the biological fate of plastics and their interaction with different biological systems. Because of the ubiquity of plastic materials in the environment and their toxic potential, it is imperative to gain reliable, regulatory-relevant, science-based data on the effects of plastic micro- and nanoparticles (PMNPs) on human health in order to implement reliable risk assessment and management strategies in the circular economy of plastics. This review presents current knowledge of human-relevant PMNP exposure doses, pathways, and toxic effects. It addresses difficulties in properly assessing plastic exposure and current knowledge gaps and proposes steps that can be taken to underpin health risk perception, assessment, and mitigation through rigorous science-based evidence. Based on the existing scientific data on PMNP adverse health effects, this review brings recommendations on the development of PMNP-specific adverse outcome pathways (AOPs) following the AOP Users' Handbook of the Organisation for Economic Cooperation and Development (OECD).

Understanding immune microenvironment alterations in the brain to improve the diagnosis and treatment of diverse brain diseases.

Abnormal inflammatory states in the brain are associated with a variety of brain diseases. The dynamic changes in the number and function of immune cells in cerebrospinal fluid (CSF) are advantageous for the early prediction and diagnosis of immune diseases affecting the brain. The aggregated factors and cells in inflamed CSF may represent candidate targets for therapy. The physiological barriers in the brain, such as the blood‒brain barrier (BBB), establish a stable environment for the distribution of resident immune cells. However, the underlying mechanism by which peripheral immune cells migrate into the brain and their role in maintaining immune homeostasis in CSF are still unclear. To advance our understanding of the causal link between brain diseases and immune cell status, we investigated the characteristics of immune cell changes in CSF and the molecular mechanisms involved in common brain diseases. Furthermore, we summarized the diagnostic and treatment methods for brain diseases in which immune cells and related cytokines in CSF are used as targets. Further investigations of the new immune cell subtypes and their contributions to the development of brain diseases are needed to improve diagnostic specificity and therapy.

Lactate administration improves laboratory parameters in murine models of iron overload.

ABSTRACT: Current iron overload therapeutics have inherent drawbacks including perpetuated low hepcidin. Here, we unveiled that lactate, a potent hepcidin agonist, effectively reduced serum and hepatic iron levels in mouse models of iron overload with an improved erythropoiesis in ß-thalassemic mice.

Exploring the relationship between hyperlactatemia and anemia.

Hyperlactatemia and anemia commonly coexist and their crosstalk is a longstanding mystery with elusive mechanisms involved in physical activities, infections, cancers, and genetic disorders. For instance, hyperlactatemia leads to iron restriction by upregulating hepatic hepcidin expression. Increasing evidence also points to lactate as a crucial signaling molecule rather than merely a metabolic byproduct. Here, we discuss the mutual influence between anemia and hyperlactatemia. This opinion calls for a reconsideration of the multifaceted roles of lactate and lactylation in anemia and emphasizes the need to fill knowledge gaps, including the dose dependence of lactate's effects, its sources, and its subcellular localization.

Zonated iron deposition in the periportal zone of the liver is associated with selectively enhanced lipid synthesis.

BACKGROUND AND AIMS: Disorders in liver lipid metabolism have been implicated in a range of metabolic conditions, including fatty liver and liver cancer. Altered lipid distribution within the liver, shifting from the pericentral to the periportal zone under pathological circumstances, has been observed; however, the underlying mechanism remains elusive. Iron, an essential metal, exhibits a zonal distribution in the liver similar to that of lipids. Nevertheless, the precise relationship between iron and lipid distribution, especially in the pericentral and periportal zones, remains poorly understood. METHODS: We conducted comprehensive in vitro and in vivo experiments, combining with in situ analysis and RNA sequencing, aiming for a detailed exploration of the causal relationship between iron accumulation and lipid metabolism. RESULTS: Our research suggests that iron overload can disrupt the normal distribution of lipids within the liver, particularly in the periportal zone. Through meticulous gene expression profiling in both the pericentral and periportal zones, we identified pyruvate carboxylase (PC) as a pivotal regulator in iron overload-induced lipid accumulation. Additionally, we revealed that the activation of cyclic adenosine monophosphate response element binding protein (CREB) was indispensable for Pc gene expression when in response to iron overload. CONCLUSIONS: In summary, our investigation unveils the crucial involvement of iron overload in fostering hepatic lipid accumulation in the periportal zone, at least partly mediated by the modulation of Pc expression. These insights offer new perspectives for understanding the pathogenesis of fatty liver diseases and their progression.

Facile Preparation of Carbohydrate-Containing Adjuvants Based on Self-Assembling Glycopeptide Conjugates.

Carbohydrates are intriguing biomolecules possessing diverse biological activities, including immune stimulating capability. However, their biomedical applications have been limited by their complex and heterogeneous structures. In this study, we have utilized a self-assembling glycopeptide conjugate (GPC) system to produce uniform nanoribbons appending homogeneous oligosaccharides with multivalency. This system successfully translates the nontrivial structural differences of oligomannoses into varied binding affinities to C-type lectin receptors (CLRs). We have shown that GPCs could promote the CLR-mediated endocytosis of ovalbumin (OVA) antigen, and two mannotriose-modified peptides F3m2 and F3m5 exhibit potent activity in inducing antigen-presenting cell maturation, as indicated by increased CD86 and MHCII expression. In vivo studies demonstrated that GPCs, combined with OVA antigen, significantly enhanced OVA-specific antibody production. Specifically, F3m2 and F3m5 exhibited the highest immunostimulatory effects, eliciting both Th1- and Th2-biased immune responses and promoting differentiation of CD4+ and CD8+  T cells. These findings highlight the potential of GPCs as vaccine adjuvants, and showcase their versatility in exploiting the biological functions of carbohydrates.

Microplastics and Nanoplastics Impair the Biophysical Function of Pulmonary Surfactant by Forming Heteroaggregates at the Alveolar-Capillary Interface.

Microplastics (MPs) are ubiquitous environmental pollutants produced through the degradation of plastic products. Nanoplastics (NPs), commonly coexisting with MPs in the environment, are submicrometer debris incidentally produced from fragmentation of MPs. We studied the biophysical impacts of MPs/NPs derived from commonly used commercial plastic products on a natural pulmonary surfactant extracted from calf lung lavage. It was found that in comparison to MPs/NPs derived from lunch boxes made of polypropylene or from drinking water bottles made of poly(ethylene terephthalate), the MP/NP derived from foam packaging boxes made of polystyrene showed the highest adverse impact on the biophysical function of the pulmonary surfactant. Accordingly, intranasal exposure of MP/NP derived from the foam boxes also induced the most serious proinflammatory responses and lung injury in mice. Atomic force microscopy revealed that NP particles were adsorbed on the air-water surface and heteroaggregated with the pulmonary surfactant film. These results indicate that although the incidentally formed NPs only make up a small mass fraction, they likely play a predominant role in determining the nano-bio interactions and the lung toxicity of MPs/NPs by forming heteroaggregates at the alveolar-capillary interface. These findings may provide novel insights into understanding the health impact of MPs and NPs on the respiratory system.

Mechanisms underlying linear ubiquitination and implications in tumorigenesis and drug discovery.

Linear ubiquitination is a distinct type of ubiquitination that involves attaching a head-to-tail polyubiquitin chain to a substrate protein. Early studies found that linear ubiquitin chains are essential for the TNFα- and IL-1-mediated NF-κB signaling pathways. However, recent studies have discovered at least sixteen linear ubiquitination substrates, which exhibit a broader activity than expected and mediate many other signaling pathways beyond NF-κB signaling. Dysregulation of linear ubiquitination in these pathways has been linked to many types of cancers, such as lymphoma, liver cancer, and breast cancer. Since the discovery of linear ubiquitin, extensive effort has been made to delineate the molecular mechanisms of how dysregulation of linear ubiquitination causes tumorigenesis and cancer development. In this review, we highlight newly discovered linear ubiquitination-mediated signaling pathways, recent advances in the role of linear ubiquitin in different types of cancers, and the development of linear ubiquitin inhibitors. Video Abstract.

IMM47, a humanized monoclonal antibody that targets CD24, exhibits exceptional anti-tumor efficacy by blocking the CD24/Siglec-10 interaction and can be used as monotherapy or in combination with anti-PD1 antibodies for cancer immunotherapy.

This study evaluates the anti-tumor mechanism of IMM47, a humanized anti-CD24 mAb. Biolayer interferometry, ELISA and flow cytometry methods were used to measure the IMM47 binding, affinity, ADCC, ADCP, ADCT and CDC activities. In vivo therapeutical efficacy was measured in transplanted mouse models. IMM47 significantly binds granulocytes but not human erythrocytes and blocks CD24's ability to bind to Siglec-10. IMM47 has strong ADCC, ADCT and ADCP activity against REH cells. IMM47's in vivo pharmacodynamics showed that IMM47 has strong anti-tumor effects in human siglec-10 transgenic mouse models with a memory immune response. IMM47 also has powerful synergistic therapeutic efficacy when combined with Tislelizumab, Opdivo and Keytruda, by blocking CD24/Siglec-10 interaction through macrophage antigen presentation with strong ADCC, ADCP, ADCT and CDC activities and with a safe profile. IMM47 binding to CD24 is independent of N-glycosylation modification of the extracellular domain.

Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice.

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.