Nuclear Regulatory Research Articles

Sugar status in preexisting leaves determines systemic stomatal development within newly developing leaves

Stomata are pores found in the epidermis of stems or leaves that modulate both plant gas exchange and water/nutrient uptake. The development and function of plant stomata are regulated by a diverse range of environmental cues. However, how carbohydrate status in preexisting leaves might determine systemic stomatal formation within newly developing leaves has remained obscure. The glucose (Glc) sensor HEXOKINASE1 (HXK1) has been reported to decrease the stability of an ethylene/Glc signaling transcriptional regulator, EIN3 (ETHYLENE INSENSITIVE3). EIN3 in turn directly represses the expression of SUC2 (sucrose transporter 2), encoding a master transporter of sucrose (Suc). Further, KIN10, a nuclear regulator involved in energy homeostasis, has been reported to repress the transcription factor SPCH (SPEECHLESS), a master regulator of stomatal development. Here, we demonstrate that the Glc status of preexisting leaves determines systemic stomatal development within newly developing leaves by the HXK1-¦EIN3-¦SUC2 module. Further, increasing Glc levels in preexisting leaves results in a HXK1-dependent decrease of EIN3 and increase of SUC2, triggering the perception, amplification and relay of HXK1-dependent Glc signaling and thereby triggering Suc transport from mature to newly developing leaves. The HXK1-¦EIN3-¦SUC2 molecular module thereby drives systemic Suc transport from preexisting leaves to newly developing leaves. Subsequently, increasing Suc levels within newly developing leaves promotes stomatal formation through the established KIN10⟶ SPCH module. Our findings thus show how a carbohydrate signal in preexisting leaves is sensed, amplified and relayed to determine the extent of systemic stomatal development within newly developing leaves.

Empirical and mechanistic transient fission gas release model for high-burnup LOCA conditions

In response to the nuclear industry desire to extend burnup beyond current licensing practices, the US Nuclear Regulatory Commission (NRC) released a research information letter (RIL) that provides a basis for analyzing fuel fragmentation, relocation, and dispersal (FFRD) in light-water reactors. Of the five elements discussed, the most ambiguous is the significance of transient fission gas (FG) release (FGR) (tFGR) and its effects on fuel performance under loss-of-coolant accident conditions. In fresh fuel, FG migration and eventual release is primarily governed by diffusion-based mechanisms at higher temperatures (>1,000 °C). However, the mechanisms governing FGR changes as burnup increases. More recent research indicates that FGR increases as burnup increases, specifically under temperature transient conditions, and this release occurs at lower temperatures with a new release mechanism. This behavior has been attributed to microcracking in the fuel and is likely related to microstructure embrittlement with the presence of over pressurized FG bubbles. The NRC RIL outlines the complexity of the phenomenon and a need for a deeper understanding to adequately address FFRD for regulatory application. Therefore, this manuscript intends to summarize the publicly available tFGR data and discuss the observed dependencies (e.g., burnup, heating rate, sample geometry, terminal temperature). An empirical model has been developed and benchmarked against recently published experimental data. However, this empirical model is limited to conditions for which fitting data exist and, therefore, a high-level discussion is included to provide a roadmap for atomistically-informed multiscale modeling in conjunction with experimental data collection to develop a mechanistic tFGR model widely applicable to a broad range of nuclear fuel conditions at high burnup.

Reliability Assessment of NPP Safety Class Equipment Considering the Manufacturing Quality Assurance Process

Quality and safety are intensely related and go hand in hand. Quality of the safety-grade equipment is very important for the safety of a nuclear power plant (NPP) and achieving production goals. During manufacturing of plant components or equipment, deviation from the design might occur at different stages of manufacturing for various reasons, such as a lack of skilled manpower, deviation of materials, human errors, malfunction of equipment, violation of manufacturing procedure, etc. These deviations can be assessed cautiously and taken into consideration in the final safety analysis report (FSAR) before issuing an operating license. In this paper, we propose a Bayesian belief network for quality assessment of safety class equipment of NPPs with a few examples. The proposed procedure is a holistic approach for estimation of equipment failure probability considering manufacturing deviations and errors. Case studies for safety-class dry transformers and reactor pressurizers employing the proposed method are also presented in this article. This study provides insights for probabilistic safety assessment engineers and nuclear plant regulators for improved assessment of NPP safety.

Panaxytriol upregulates CYP3A4 expression through the interaction between nuclear regulators and DNA response elements.

Cytochrome P3A4 (CYP3A4) is a crucial drug-metabolizing enzyme, and its expression is regulated by the pregnane X receptor (PXR), constitutive androstane receptor (CAR), steroid receptor coactivator 1 (SRC-1), and acetyltransferase P300. Panaxytriol is a naturally derived active substance extracted from the roots of Panax ginseng C. A. Mey. which is widely used clinically. Our previous studies have shown that panaxytriol induces CYP3A4 expression through PXR activation, which is antagonized by high CAR expression. However, the underlying mechanism remains unclear. This study aimed to investigate the mechanism of panaxytriol in inducing CYP3A4 expression via interactions between nuclear regulators and DNA response elements. Immunoprecipitation technique was used to assess the binding levels of PXR and CAR with the coactivators SRC-1 and P300 in HepG2 and Huh-7cells. Furthermore, chromatin immunoprecipitation assay was used to investigate the PXR and CAR interaction with the CYP3A4 promoter response element ER-6/DR-3. The binding of PXR to SRC-1, P300, and the response elements ER-6 and DR-3 was improved with an increase in panaxytriol concentration (10-80μM), and the binding affinity was further enhanced upon CAR silencing. The binding of CAR to SRC-1 and the response elements ER-6 and DR-3 was significantly higher at 80μM panaxytriol, whereas no significant binding was observed between CAR and P300. Panaxytriol promoted the recruitment of PXR to SRC-1 and P300, binding to ER-6 and DR-3, and upregulating CYP3A4 expression. Furthermore, an interactive dialogue regulatory mechanism between PXR and CAR was observed.

Y-complex nucleoporins independently contribute to nuclear pore assembly and gene regulation in neuronal progenitors.

Besides assembling nuclear pore complexes, the conduits of nuclear transport, many nucleoporins also contribute to chromatin organization and gene expression, with critical roles in development and pathologies. We previously reported that Nup133 and Seh1, two components of the Y-complex subassembly of the nuclear pore scaffold, are dispensable for mouse embryonic stem cell viability but required for their survival during neuroectodermal differentiation. Here, a transcriptomic analysis revealed that Nup133 regulates a subset of genes at early stages of neuroectodermal differentiation, including Lhx1 and Nup210L, encoding a newly validated nucleoporin. These genes are also misregulated in Nup133▵Mid neuronal progenitors, in which nuclear pore basket assembly is impaired. However, a four-fold reduction of Nup133, despite also affecting basket assembly, is not sufficient to alter Nup210L and Lhx1 expression. Finally, these two genes are also misregulated in Seh1-deficient neural progenitors only showing a mild reduction in nuclear pore density. Together these data reveal a shared function of Y-complex nucleoporins in gene regulation during neuroectodermal differentiation, apparently independent of nuclear pore basket integrity.

Comparative Maps of Safety Features for Fission and Fusion Reactors

Abstract The differences between nuclear fission and fusion have been discussed widely in the literature. However, little has been done to investigate the key differences in safety designs and regulatory requirements between the nuclear reactor types. In this study, an innovative methodology was successfully developed to map nuclear safety features to the fundamental safety principles set out by the nuclear regulators. Three safety cases were assessed in the mapping study, a research fusion reactor (Joint European Torus), a research fission reactor (Tsing Hua Open-pool Reactor) and a commercial fission reactor (Hinkley Point C). The graphical representation allowed a comparative analysis of the safety features and fundamental principles which revealed differences between the hazard profiles of fission and fusion reactors and provided important insights for the creation of a similar map for a future commercial fusion device.

BISON validation to in situ cladding burst test and high-burnup LOCA experiments

The process for developing and qualifying nuclear fuels for commercial nuclear application requires fundamental material development, characterization, and design; out-of-pile testing on unirradiated materials; integral fuel rod irradiations, testing, and postirradiation examinations; and transient analyses. The historical approach depends on the generation of large empirical datasets and series of integral fuel rod irradiations, and this approach ultimately takes ∼20 years—or sometimes longer—to acquire data through extensive sequential testing. Thus, the qualification and eventual deployment of new fuel systems constitute a long process. However, recent technological advancements have provided researchers the opportunity to perform out-of-cell, in situ measurements to assess material performance for the duration of the experiment. One such example of this capability is the use of digital image coordination and thermal imaging to assess Zircaloy cladding performance under a simulated loss-of-coolant accident (LOCA) transient condition. In situ measurements generally provide high-fidelity strain, strain rates, and temperature surface maps. This is critical for the US nuclear industry, which is actively developing a technical basis to support extending the peak rod average burnup from 62 to ∼75 GWd/tU and the deployment of accident-tolerant fuel. However, the US Nuclear Regulatory Commission (NRC) outlined in its research information letter several technical issues that the industry must address before extending burnup. One topic of specific interest is understanding the cladding balloon and rupture geometry during the LOCA heat-up phase. By leveraging these advanced in situ capabilities, this work used in situ data generated from a simulated LOCA to better understand high-temperature creep and its effect on Zircaloy balloon and rupture performance. This work used the BISON fuel performance code to assess the high-temperature creep model predictions with in situ data.

Identification of epigenetic modulators as determinants of nuclear size and shape.

The shape and size of the human cell nucleus is highly variable among cell types and tissues. Changes in nuclear morphology are associated with disease, including cancer, as well as with premature and normal aging. Despite the very fundamental nature of nuclear morphology, the cellular factors that determine nuclear shape and size are not well understood. To identify regulators of nuclear architecture in a systematic and unbiased fashion, we performed a high-throughput imaging-based siRNA screen targeting 867 nuclear proteins including chromatin-associated proteins, epigenetic regulators, and nuclear envelope components. Using multiple morphometric parameters, and eliminating cell cycle effectors, we identified a set of novel determinants of nuclear size and shape. Interestingly, most identified factors altered nuclear morphology without affecting the levels of lamin proteins, which are known prominent regulators of nuclear shape. In contrast, a major group of nuclear shape regulators were modifiers of repressive heterochromatin. Biochemical and molecular analysis uncovered a direct physical interaction of histone H3 with lamin A mediated via combinatorial histone modifications. Furthermore, disease-causing lamin A mutations that result in disruption of nuclear shape inhibited lamin A-histone H3 interactions. Oncogenic histone H3.3 mutants defective for H3K27 methylation resulted in nuclear morphology abnormalities. Altogether, our results represent a systematic exploration of cellular factors involved in determining nuclear morphology and they identify the interaction of lamin A with histone H3 as an important contributor to nuclear morphology in human cells.

Dow nuclear reactor set for Texas

Dow has selected its petrochemical complex in Seadrift, Texas, as the site to install a small modular nuclear reactor system designed by X-Energy Reactor. The reactor will supply electricity and steam for the complex and will save about 440,000 metric tons of carbon dioxide emissions per year. The companies are now preparing permits for the Nuclear Regulatory Commission. They expect to begin construction in 2026 and complete the project by the end of the decade.

Activation Analysis for the Inboard Region of FNSF Using SERPENT

This study describes an application of the SERPENT 2 code with the TENDL-2017 nuclear data library and the latest available model features of the Fusion Energy System Studies–Fusion Nuclear Science Facility (FNSF), to evaluate the activation of components after shutdown at 1, 10, and 100 years, assuming a plant lifetime of 8.5 full-power years. The primary parameters evaluated include the specific activity, decay heat, and waste disposal rating (WDR). The specific activity and decay heat are calculated with SERPENT 2 using a 360-deg model of the FNSF, while the WDR is calculated and classified based on the waste disposal limits established by the U.S. Nuclear Regulatory Commission under 10 CFR 61.55 as well as by using the Fetter approach. A python-based script developed for a previous high-level waste classification and analysis study was implemented and adapted to this research to calculate the WDR by comparing nuclide concentrations to the values established in 10 CFR 61.55 to generate a waste classification for each component surveyed. As only three short-lived isotopes have limitations for classifications beyond Class A, of which only 63Ni is present in appreciable quantities, there is a limit to the amount that short-lived isotopes contribute to the most significant waste analyzed here. In most cases, a handful of long-lived isotopes can be problematic, such as 59Ni and 94Nb, for example, which are solely responsible for multiple Class C classifications. The results herein reported heavily depend on the specific materials and mass/volume fractions in the specific model used in this study, which has changed and evolved since the inception of the FNSF concept and past studies. Therefore, the more significant contributions of this study may be the development of a modeling and simulation toolkit and a strategy to perform these calculations, so to help evaluate and optimize future fusion facilities.

Role of the plant-specific calcium-binding C2-DOMAIN ABSCISIC ACID-RELATED (CAR) protein family in environmental signaling

Many signaling processes rely on information decoding at the plasma membrane, and membrane-associated proteins and their complexes are fundamental for regulating this process. Still many questions exist as to how protein complexes are assembled and function at membrane sites to change identity and dynamics of membrane systems. Peripheral membrane proteins containing a calcium and phospholipid-binding C2-domain can act in membrane-related signaling by providing a tethering function so that protein complexes form. C2 domain proteins termed C2-DOMAIN ABSCISIC ACID-RELATED (CAR) proteins are plant-specific, and the functional relevance of this C2 domain protein subgroup is just emerging. The ten Arabidopsis CAR proteins CAR1 to CAR10 have a single C2 domain with a plant-specific insertion, the so-called “CAR-extra-signature” or also termed “sig domain”. Via this “sig domain” CAR proteins can bind signaling protein complexes of different kinds and act in biotic and abiotic stress, blue light and iron nutrition. Interestingly, CAR proteins can oligomerize in membrane microdomains, and their presence in the nucleus can be linked with nuclear protein regulation. This shows that CAR proteins may play unprecedented roles in coordinating environmental responses and assembling required protein complexes to transmit information cues between plasma membrane and nucleus. The aim of this review is to summarize structure-function characteristics of the CAR protein family and assemble findings from CAR protein interactions and physiological functions. From this comparative investigation we extract common principles about the molecular operations that CAR proteins may fulfill in the cell. We also deduce functional properties of the CAR protein family based on its evolution and gene expression profiles. We highlight open questions and suggest novel avenues to prove and understand the functional networks and roles played by this protein family in plants.

A greedy algorithm for wavelet-based time domain response spectrum matching

U.S. Nuclear Regulatory Commission NUREG-0800, “Standard Review Plan,” Section 3.7.1, “Seismic Design Parameters,” Revision 4, describes acceptance criteria for seismic design time histories, including response spectrum matching and checking power spectral density functions. This paper is a focused introduction of a new algorithm developed for response spectrum matching, named as the Greedy Wavelet Method (GWM), which shows substantial advances in convergence characteristics over the RspMatch09 program. RspMatch09 is widely used by the nuclear industry and represents the results of multiple iterations of enhancement by international researchers since the basic method was first introduced in 1978. GWM modifies a seed acceleration time history by adding just one wavelet in each iteration, in contrast to RspMathc09 that adds a set of weighted wavelets, with the weights determined by solving an optimization problem in each iteration. GWM includes procedures to address two specific issues leading to convergence difficulties in response spectrum matching: The shape of the wavelets can be numerically distorted at high frequencies and the wavelet lead time previously recommended is not sufficiently long. These newly developed procedures made GWM unconditionally stable. For the benchmark problem, GWM was demonstrated to save 99.5% of the wavelets required by RspMatch09. We also implemented in GWM several advanced, interactive tools to perform baseline corrections and other related tasks. Examples provided in this paper are for demonstration purposes only.

Changing course: Glucose starvation drives nuclear accumulation of Hexokinase 2 in S. cerevisiae.

Glucose is the preferred carbon source for most eukaryotes, and the first step in its metabolism is phosphorylation to glucose-6-phosphate. This reaction is catalyzed by hexokinases or glucokinases. The yeast Saccharomyces cerevisiae encodes three such enzymes, Hxk1, Hxk2, and Glk1. In yeast and mammals, some isoforms of this enzyme are found in the nucleus, suggesting a possible moonlighting function beyond glucose phosphorylation. In contrast to mammalian hexokinases, yeast Hxk2 has been proposed to shuttle into the nucleus in glucose-replete conditions, where it reportedly moonlights as part of a glucose-repressive transcriptional complex. To achieve its role in glucose repression, Hxk2 reportedly binds the Mig1 transcriptional repressor, is dephosphorylated at serine 15 and requires an N-terminal nuclear localization sequence (NLS). We used high-resolution, quantitative, fluorescent microscopy of live cells to determine the conditions, residues, and regulatory proteins required for Hxk2 nuclear localization. Countering previous yeast studies, we find that Hxk2 is largely excluded from the nucleus under glucose-replete conditions but is retained in the nucleus under glucose-limiting conditions. We find that the Hxk2 N-terminus does not contain an NLS but instead is necessary for nuclear exclusion and regulating multimerization. Amino acid substitutions of the phosphorylated residue, serine 15, disrupt Hxk2 dimerization but have no effect on its glucose-regulated nuclear localization. Alanine substation at nearby lysine 13 affects dimerization and maintenance of nuclear exclusion in glucose-replete conditions. Modeling and simulation provide insight into the molecular mechanisms of this regulation. In contrast to earlier studies, we find that the transcriptional repressor Mig1 and the protein kinase Snf1 have little effect on Hxk2 localization. Instead, the protein kinase Tda1 regulates Hxk2 localization. RNAseq analyses of the yeast transcriptome dispels the idea that Hxk2 moonlights as a transcriptional regulator of glucose repression, demonstrating that Hxk2 has a negligible role in transcriptional regulation in both glucose-replete and limiting conditions. Our studies define a new model of cis- and trans-acting regulators of Hxk2 dimerization and nuclear localization. Based on our data, the nuclear translocation of Hxk2 in yeast occurs in glucose starvation conditions, which aligns well with the nuclear regulation of mammalian orthologs. Our results lay the foundation for future studies of Hxk2 nuclear activity.

Fukushima: Lessons learned from a devastating “near-miss”

ABSTRACT Before the Fukushima disaster unfolded in 2011, Japanese government and energy company officials were aware of the warning signs and risks of a potential crisis at the reactor site. They failed to use safety mechanisms or update regulations over time to address the vulnerabilities of the power plants. Because interest groups had led the public to believe the power plants were completely safe, the plants were run with little accountability. Following this disaster, Japan established a new nuclear regulatory commission and nuclear regulatory authority in and implemented new regulatory mechanisms. These efforts have been limited, however, and have shifted the issue from regulation to implementation. The enormous cost of meeting new safety protocols has created new barriers for restarting the power plants under updated regulations, but the energy demands of the country will remain. The tension between managing operational risks and meeting public energy needs will test the public and private sectors’ ability to sufficiently revamp the nuclear industry and prevent crises in years to come.

Key nuclear data for non-LWR reactivity analysis

An assessment of nuclear data performance for non-light-water reactor (non-LWR) reactivity calculations was performed at Oak Ridge National Laboratory that involved a thorough literature review to collect related observations made across different research institutions, an interrogation of the latest ENDF/B evaluated nuclear data libraries, and propagation of nuclear data uncertainties to key figures of merit associated with reactor safety for six non-LWR benchmarks. The outcome of this comprehensive study was published in a technical report issued by the US Nuclear Regulatory Commission. This paper provides a summary of the study’s key observations and conclusions and demonstrates with two examples how the various methods available in the SCALE code system were used to identify key cross section uncertainties for non-LWR reactivity analyses.

Deep learning health management diagnostics applied to the NIST smoke experiments

Fire is one of the most important hazards that must be considered in advanced nuclear power plant safety assessments. The Nuclear Regulatory Commission (NRC) has developed a large collection of experimental data and associated analyses related to the study of fire safety. In fact, computational fire models are based on quantitative comparisons to those experimental data. During the modeling process, it is important to develop diagnostic health management systems to check the equipment status in fire processes. For example, a fire sensor does not directly provide accurate and complex information that nuclear power plants (NPPs) require. With the assistance of the machine learning method, NPP operators can directly get information on local, ignition, fire material of an NPP fire, instead of temperature, smoke obscuration, gas concentration, and alarm signals. In order to improve the predictive capabilities, this work demonstrates how the deep learning classification method can be used as a diagnostic tool in a specific set of fire experiments. Through a single input from a sensor, the deep learning tool can predict the location and type of fire. This tool also has the capability to provide automatic signals to potential passive fire safety systems. In this work, test data are taken from a specific set of the National Institute of Standards and Technology (NIST) fire experiments in a residential home and analyzed by using the machine learning classification models. The networks chosen for comparison and evaluation are the dense neural networks, convolutional neural networks, long short-term memory networks, and decision trees. The dense neural network and long short-term memory network produce similar levels of accuracy, but the convolutional neural network produces the highest accuracy.

Can Tritium Monitoring and Control Requirements for DEMO Be Met by Existing Technologies?

The tritium inventory of future fusion power plants needs to be monitored in the fuel cycle for several reasons: to comply with limits imposed by environment and safety regulators, to adhere to practices required by nuclear regulators, and for process control purposes. Fulfilling all these requirements leads to a comprehensive list of locations in the fuel cycle where tritium monitoring needs to take place, each characterized by different measurement conditions and required accuracies. Meanwhile, existing tritium detection technologies all come with specific applicabilities such as accuracy, material phase, and ability to detect tritium in a continuous manner. These do not necessarily correspond to the required measurement conditions. As an example, one tritium detection technology will be matched up with the previously defined measurement conditions, which allows for the identification of gaps in the existing detection capabilities of this technology. This work leads to several recommendations, i.e., developments to expand the applicability of tritium detection technologies, experimental proposals to test detection techniques at more extreme conditions, and expansion of the regulatory framework regarding tritium handling and breeding. These developments are critical for a functioning tritium management and control system, and this paper outlines the first step in that process.

Reactive Oxygen Species Control Osteoblast Apoptosis through SIRT1/PGC-1α/P53Lys382 Signaling, Mediating the Onset of Cd-Induced Osteoporosis.

The imbalance between osteogenesis and osteoclastogenesis is a feature of bone metabolic disease. Cadmium (Cd) exposure causes human bone loss and osteoporosis (OP) through bioaccumulation of the food chain. However, the impact of Cd on bone tissues and the underlying molecular mechanisms are not well-characterized. In the current study, we found that the Cd concentration in bone tissues of OP patients was higher than normal subjects; meanwhile, the nuclear silent information regulator of transcription 1 (SIRT1) protein expression level was significantly decreased, which is a new star molecule to treat OP. It is further revealed that SIRT1 activation markedly reprograms bone metabolic and stress-response pathways that incline with osteoblast (OB) apoptosis. Suppressing reactive oxygen species (ROS) release with N-acetyl-l-cysteine (NAC) abolished Cd-induced reduction of SIRT1 protein, deacetylation of P53, OB apoptosis, and attenuated OP. Conversely, overexpression of SIRT1 suppressed Cd-induced ROS release. SIRT1 overexpression in vivo and in vitro dampened PGC-1α protein, acetylation of P53 at lysine 382, and caspase-dependent apoptosis. These results reveal that ROS/SIRT1 controls P53 acetylation and coordinates OB apoptosis involved in the onset of OP.

Impact of Site-Response Characterization on Probabilistic Seismic Hazard in the Po Plain (Italy)

ABSTRACT We present a probabilistic seismic hazard analysis (PSHA) for the entire Po Plain sedimentary basin (Italy)—one of the widest Quaternary alluvial basins of Europe, to evaluate the impact of site-response characterization on hazard estimates. A large-scale application of approach 3 of the U.S. Nuclear Regulatory Commission (NRC) to include seismic amplification in the hazard is presented. Both 1D amplification related to stratigraphic conditions and 3D amplification due to basin effects are considered with the associated uncertainties, and their impact on the hazard is analyzed through a sensitivity analysis. Whereas 3D basin effects are considered through the application of an empirical, spatial invariant correction term, 1D amplification was estimated throughout the study area by means of dynamic (equivalent linear) ground-response analysis. To separate aleatory variabilities and epistemic uncertainties related to site response, a partially nonergodic approach is used. The results provide a finer picture of the actual seismic hazard, highlighting those areas where the ground motion is affected by amplification effects due to local or regional geological features. We found that, for a return period of 475 yr, neglecting basin effects produces a 30% underestimation of the seismic hazard in the long-period (>1 s) range. Moreover, with reference to the hazard model adopted, such effects are responsible for most of the epistemic uncertainty (up to 80%) in the results. Therefore, such effects deserve special attention in future research related to PSHA in the Po Plain sedimentary basin.

Abstract 3070: Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced prostate cancer

Abstract Advanced prostate cancer is a heterogeneous disease driven by diverse genetic alterations, with metastasis and lethal progression as the inevitable outcome. We observed that a subset of clinical primary prostate cancer is markedly reduced for SULT2B1b (SULT2B) sulfotransferase, which is an oxysterol-sulfating enzyme. Metastasized castration-resistant prostate cancer (CRPC) uniformly lacks SULT2B. Oxysterols are oxidized cholesterol metabolites and in agonist function, they activate liver X receptors (LXRα/β), which are members of the nuclear receptor family and regulators of lipogenesis, cholesterol homeostasis and immune functions. LXR signaling is enzymatically inhibited by SULT2B activity since sulfated oxysterols are LXR-inert. We previously reported that genetic silencing of SULT2B led to escalated CRPC proliferation; enhanced xenograft tumor growth; increased cell migration, invasion; reduced stiffness, adhesiveness; and EMT activation. SULT2B-depleted CRPC cells showed robust upregulation of AKR1C3 aldo-keto reductase and AKR1C3-dependent activation of the ERK1/2 survival signal. AKR1C3 regulates intratumoral androgen biosynthesis, and it is known to be elevated in advanced prostate cancer. In the current study, we validate our previous result by showing that ectopic expression of SULT2B caused AKR1C3 reduction in CRPC cells. Mechanistically, we observed that enhanced AKR1C3 expression in SULT2B-depleted cells was prevented upon genetic or pharmacologic inactivation of LXR. In addition, ERRα, another non-steroid nuclear receptor, was reduced in LXR-inactivated cells and notably, AKR1C3 was reduced in CRPC cells upon ERRα degradation by an ERRα-selective PROTAC. The LXR dependence of ERRα and AKR1C3 expression was observed in both androgen receptor expressing and non-expressing CRPC cells. Conclusion & Translational Significance: Above results reveal a novel LXR-ERRα-AKR1C3-ERK axis which is activated in SULT2B-deficient CRPC cells irrespective of the androgen receptor status of these cells. Notably, elevated ERRα portends poor prognosis for prostate cancer and cholesterol is an ERRα agonist. Considering that statin can diminish ERRα activity (PMID 26777690) and AKR1C3 inhibitors are in clinical trials, this novel axis revealed from our study may be actionable for the clinical interception of the progression in SULT2B-low advanced prostate cancer. Citation Format: Bobae Park, Katarzyna Knapczyk-Stwora, Yaguang Liu, Chung S. Song, Bandana Chatterjee. Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3070.