Nonclassical Target Research Articles

Interactions between PTH and adiposity: appetizing possibilities.

Although parathyroid hormone (PTH) is best known for its role as a regulator of skeletal remodelling and calcium homeostasis, more recent evidence supports a role for it in energy metabolism and other non-classical targets. In this report, we summarize evidence for an effect of PTH on adipocytes. This review is based upon all peer-reviewed papers, published in the English language with PubMed as the primary search engine. Recent preclinical studies have documented an effect of PTH to stimulate lipolysis in both adipocytes and liver cells and to cause browning of adipocytes. PTH also reduces bone marrow adiposity and hepatic steatosis. Although clinical studies are limited, disease models of PTH excess and PTH deficiency lend support to these preclinical findings. This review supports the concept of PTH as a polyfunctional hormone that influences energy metabolism as well as bone metabolism.

Atypical pituitary hormone-target tissue axis.

A long-held belief is that pituitary hormones bind to their cognate receptors in classical target glands to actuate their manifold functions. However, a number of studies have shown that multiple types of pituitary hormone receptors are widely expressed in non-classical target organs. Each pituitary gland-derived hormone exhibits a wide range of nonconventional biological effects in these non-classical target organs. Herein, the extra biological functions of pituitary hormones, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, adrenocorticotrophic hormone, and prolactin when they act on non-classical organs were summarized, defined by the novel concept of an "atypical pituitary hormone-target tissue axis." This novel proposal explains the pathomechanisms of abnormal glucose and lipid metabolism, obesity, hypertension, fatty liver, and atherosclerosis while offering a more comprehensive and systematic insights into the coordinated regulation of environmental factors, genetic factors, and neuroendocrine hormones on human biological functions. The continued exploration of the physiology of the "atypical pituitary hormone-target tissue axis" could enable the identification of novel therapeutic targets for metabolic diseases.

The mineralocorticoid receptor modulates timing and location of genomic binding by glucocorticoid receptor in response to synthetic glucocorticoids in keratinocytes.

Glucocorticoids (GCs) exert potent antiproliferative and anti-inflammatory properties, explaining their therapeutic efficacy for skin diseases. GCs act by binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in classical and non-classical targets including keratinocytes. Using knockout mice, we previously demonstrated that GR and MR exert essential nonoverlapping functions in skin homeostasis. These closely related receptors may homo- or heterodimerize to regulate transcription, and theoretically bind identical GC-response elements (GRE). We assessed the contribution of MR to GR genomic binding and the transcriptional response to the synthetic GC dexamethasone (Dex) using control (CO) and MR knockout (MREKO ) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO , with significantly decreased GRE enrichment, and reduced nuclear GR. Surface plasmon resonance determined steady state affinity constants, suggesting preferred dimer formation as MR-MR > GR-MR ~ GR-GR; however, kinetic studies demonstrated that GR-containing dimers had the longest lifetimes. Despite GR-binding differences, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC transcriptional responses in keratinocytes.

Vitamin D: Structure and mechanism of action

Vitamin D has received more attention in recent years as a result of the resurgence of vitamin D deficiency and rickets as a global health issue, as well as compelling evidence in the laboratory indicating that 1,25-dihydroxy vitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin D, generates several extraskeletal biological responses such as inhibition of breast, colon, and prostate cancer cell progression; effects on the cardiovascular system; and protects against. This review covers our present knowledge of vitamin D and its bioactivation, as well as fresh findings that have altered our understanding of vitamin D activity in both classical and nonclassical target tissues. This page also assesses vitamin D's alleged involvement in extraskeletal health, provides an overview of 1,25(OH)2D3 analogs that have been created, and highlights unanswered problems.

Metabolic features of young patients with primary hyperparathyroidism

Background: The main components of mineral metabolism can influence non-classical target organs such as adipose tissue, pancreas, vascular wall. The «metabolic» effects of parathyroid hormone (PTH) and other participants of phosphorus-calcium metabolism in the hyperfunction of parathyroid glands remain unclear. The study of disorders of carbohydrate, fat and other types of metabolism in primary hyperparathyroidism (PHPT) will help to develop effective measures for prophylaxis and treatment of the patients in order to improve the quality and life span of the population.Aim: To study the main parameters of metabolism in young patients with an active stage of PHPT before surgical treatment.Materials and methods: A one-stage comparative study of young patients with PHPT and healthy volunteers matched by sex, age and body mass index (BMI) was carried out. The participants underwent a comprehensive biochemical and hormonal examination, a hyperinsulinemic euglycemic clamp and a bioimpedance analysis of the body composition.Results: 21 patients with PHPT and 18 healthy volunteers were included in the study. Patients with PHPT have higher level of serum triglycerides (p=0.003) without statistically differences of the main carbohydrate and purine parameters comparing with the control group. Visceral obesity were revealed in 42.9% of patients, including those with a normal BMI. Insulin resistance in the PHPT group was noted in 52.4% of cases, while the M-index was statistically lower than in the control subgroup (p=0.008), despite of the comparable body composition of the participants. The M-index showed a positive correlation with blood phosphorus level (p=0.010) only in the general group. Statistically positive correlations of PTH, albumin-corrected calcium and osteocalcin with triglyceride levels, calcium with fasting glycaemia, and PTH with uric acid levels were determined.Conclusion: PHPT is associated with insulin resistance in patients that is the main risk factor for the development of serious carbohydrate and fat disorders. The positive correlation of PTH and blood calcium levels with triglycerides, as well as the tendency to hypertriglyceridemia comparing with healthy volunteers, suggest the disease effect on the development of dyslipidemia.

Метаболический профиль пациентов молодого возраста с первичным гиперпаратиреозом

Background: The main components of mineral metabolism can influence non-classical target organs such as adipose tissue, pancreas, vascular wall. The «metabolic» effects of parathyroid hormone (PTH) and other participants of phosphorus-calcium metabolism in the hyperfunction of parathyroid glands remain unclear. The study of disorders of carbohydrate, fat and other types of metabolism in primary hyperparathyroidism (PHPT) will help to develop effective measures for prophylaxis and treatment of the patients in order to improve the quality and life span of the population. Aim: To study the main parameters of metabolism in young patients with an active stage of PHPT before surgical treatment. Materials and methods: A one-stage comparative study of young patients with PHPT and healthy volunteers matched by sex, age and body mass index (BMI) was carried out. The participants underwent a comprehensive biochemical and hormonal examination, a hyperinsulinemic euglycemic clamp and a bioimpedance analysis of the body composition. Results: 21 patients with PHPT and 18 healthy volunteers were included in the study. Patients with PHPT have higher level of serum triglycerides (p=0.003) without statistically differences of the main carbohydrate and purine parameters comparing with the control group. Visceral obesity were revealed in 42.9% of patients, including those with a normal BMI. Insulin resistance in the PHPT group was noted in 52.4% of cases, while the M-index was statistically lower than in the control subgroup (p=0.008), despite of the comparable body composition of the participants. The M-index showed a positive correlation with blood phosphorus level (p=0.010) only in the general group. Statistically positive correlations of PTH, albumin-corrected calcium and osteocalcin with triglyceride levels, calcium with fasting glycaemia, and PTH with uric acid levels were determined. Conclusion: PHPT is associated with insulin resistance in patients that is the main risk factor for the development of serious carbohydrate and fat disorders. The positive correlation of PTH and blood calcium levels with triglycerides, as well as the tendency to hypertriglyceridemia comparing with healthy volunteers, suggest the disease effect on the development of dyslipidemia.

The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.

The nexus of chronic kidney disease (CKD) and cardiovascular disease (CVD) amplifies the morbidity and mortality of CKD, emphasizing the need for defining and establishing therapeutic initiatives to modify and abrogate the progression of CKD and concomitant CV risks. In addition to the traditional CV risk factors, disturbances of mineral metabolism are specific risk factors that contribute to the excessive CV mortality in patients with CKD. These risk factors include dysregulations of circulating factors that modulate phosphate metabolism, including fibroblast growth factor 23 (FGF23) and soluble Klotho. Reduced circulating levels and suppressed renal Klotho expression may be associated with adverse outcomes in CKD patients. While elevated circulating concentrations or locally produced FGF23 in the strained heart exert prohypertrophic mechanisms on the myocardium, Klotho attenuates tissue fibrosis, progression of CKD, cardiomyopathy, endothelial dysfunction, vascular stiffness and vascular calcification. Mineralocorticoid receptor (MR) activation in nonclassical targets, mediated by aldosterone and other ligands, amplifies CVD in CKD. In concert, we detail how the interplay of elevated FGF23, activation of the MR and concomitant reductions of circulating Klotho in CKD may potentiate each other's deleterious effects on the kidney and heart, thereby contributing to the initiation and progression of kidney and cardiac functional deterioration, acting through multipronged, albeit complementary, mechanistic pathways.

Defining the underlying defect in insulin action in type 2 diabetes.

Insulin resistance is one of the earliest defects in the pathogenesis of type 2 diabetes. Over the past 50years, elucidation of the insulin signalling network has provided important mechanistic insights into the abnormalities of glucose, lipid and protein metabolism that underlie insulin resistance. In classical target tissues (liver, muscle and adipose tissue), insulin binding to its receptor initiates a broad signalling cascade mediated by changes in phosphorylation, gene expression and vesicular trafficking that result in increased nutrient utilisation and storage, and suppression of catabolic processes. Insulin receptors are also expressed in non-classical targets, such as the brain and endothelial cells, where it helps regulate appetite, energy expenditure, reproductive hormones, mood/behaviour and vascular function. Recent progress in cell biology and unbiased molecular profiling by mass spectrometry and DNA/RNA-sequencing has provided a unique opportunity to dissect the determinants of insulin resistance in type 2 diabetes and the metabolic syndrome; best studied are extrinsic factors, such as circulating lipids, amino acids and other metabolites and exosomal microRNAs. More challenging has been defining the cell-intrinsic factors programmed by genetics and epigenetics that underlie insulin resistance. In this regard, studies using human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway. Understanding how these multi-layered molecular networks modulate insulin action and metabolism in different tissues will open new avenues for therapy and prevention of type 2 diabetes and its associated pathologies.

Tackling Immune Targets for Breast Cancer: Beyond PD-1/PD-L1 Axis.

The burden of breast cancer is imposing a huge global problem. Drug discovery research and novel approaches to treat breast cancer have been carried out extensively over the last decades. Although immune checkpoint inhibitors are showing promising preclinical and clinical results in treating breast cancer, they are facing multiple limitations. From an immunological perspective, a recent report highlighted breast cancer as an “inflamed tumor” with an immunosuppressive microenvironment. Consequently, researchers have been focusing on identifying novel immunological targets that can tune up the tumor immune microenvironment. In this context, several novel non-classical immune targets have been targeted to determine their ability to uncouple immunoregulatory pathways at play in the tumor microenvironment. This article will highlight strategies designed to increase the immunogenicity of the breast tumor microenvironment. It also addresses the latest studies on targets which can enhance immune responses to breast cancer and discusses examples of preclinical and clinical trial landscapes that utilize these targets.

Off-Target Stoichiometric Binding Identified from Toxicogenomics Explains Why Some Species Are More Sensitive than Others to a Widely Used Neonicotinoid.

Neonicotinoids are currently licensed for use in 120 countries, making accurate nontarget species sensitivity predictions critical. Unfortunately, such predictions are fraught with uncertainty, as sensitivity is extrapolated from only a few test species and neonicotinoid sensitivities can differ greatly between closely related taxa. Combining classical toxicology with de novo toxicogenomics could greatly improve sensitivity predictions and identify unexpectedly susceptible species. We show that there is a >30-fold differential species sensitivity (DSS) for the neonicotinoid imidacloprid between five earthworm species, a critical nontarget taxon. This variation could not be explained by differential toxicokinetics. Furthermore, comparing key motif expression in subunit genes of the classical nicotinic acetylcholine receptor (nAChR) target predicts only minor differences in the ligand binding domains (LBDs). In contrast, predicted dissimilarities in LBDs do occur in the highly expressed but nonclassical targets, acetylcholine binding proteins (AChBPs). Critically, the predicted AChBP divergence is capable of explaining DSS. We propose that high expression levels of putative nonsynaptic AChBPs with high imidacloprid affinities reduce imidacloprid binding to critical nAChRs involved in vital synaptic neurotransmission. This study provides a clear example of how pragmatic interrogation of key motif expression in complex multisubunit receptors can predict observed DSS, thereby informing sensitivity predictions for essential nontarget species.

Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective.

Cannabis has been used for centuries for recreational and therapeutic purposes. Whereas, the recreative uses are based on the psychotropic effect of some of its compounds, its therapeutic effects range over a wide spectrum of actions, most of which target the brain or the immune system. Several studies have found cannabinoid receptors in the auditory system, both at peripheral and central levels, thus raising the interest in cannabinoid signaling in hearing, and especially in tinnitus, which is affected also by anxiety, memory, and attention circuits where cannabinoid effects are well described. Available studies on animal models of tinnitus suggest that cannabinoids are not likely to be helpful in tinnitus treatment and could even be harmful. However, the pharmacology of cannabinoids is very complex, and most studies focused on neural CB1R-based responses. Cannabinoid effects on the immune system (where CB2Rs predominate) are increasingly recognized as essential in understanding nervous system pathological responses, and data on immune cannabinoid targets have emerged in the auditory system as well. In addition, nonclassical cannabinoid targets (such as TRP channels) appear to play an important role in the auditory system as well. This review will focus on neuroimmunological mechanisms for cannabinoid effects and their possible use as protective and therapeutic agents in the ear and auditory system, especially in tinnitus.

Abstract B30: Joint control of epidermal cell fate by Yorkie and Bonus

Abstract Dysregulation of the Hippo pathway results in organ overgrowth and contributes to carcinogenesis in humans. Although the Hippo pathway has been intensively studied for its regulation of cell proliferation and organ growth, its role beyond growth control remains elusive. To explore possible novel functions of the Hippo pathway, we carried out an affinity purification-mass spectrometry (AP-MS) analysis in Drosophila embryos and cultured cells, using transcriptional coactivator Yorkie (Yki, YAP1 homolog) as bait. Prominent groups of identified interactors included all of the core pathway components and known accessory regulators, as well as subunits of RNA polymerase II and components of the Trithorax-related (Trr) complex. Among putative novel interactors we found Bonus (Bon), the Drosophila homolog of the mammalian transcriptional intermediary factor-1/tripartite motif containing (TIF1/TRIM24/TRIM33) family of proteins. Protein interaction between Bon and Yki requires the WW domains in Yki and PPxY motifs in Bon. Interestingly, Bon overexpression leads to formation of epidermal extensions (trichomes) on the surface of adult eyes. This phenotype requires Yki and Scalloped (Sd, TEAD homolog), as well as Bon-Yki interaction. To obtain a mechanistic understanding of this apparent switch towards an epidermal cell fate, we searched for novel genes that may be jointly regulated by Bon and Yki, and identified several candidates based on published ChIP-seq and RNA-seq analyses. These putative target genes are not canonical Hippo pathway effectors, but include factors involved in early eye specification as well as genes controlled by steroid hormone signaling. Loss or gain of function of a subset of these genes modified the trichome phenotype, suggesting that they are under the control of Bon and Yki and are involved in establishing a choice between a “generic” epidermal cell fate and eye field specification. In summary, our study reveals a novel function of the Hippo pathway in the regulation of epidermal cell differentiation. This regulation occurs through the interaction between Yki and Bon as well as their joint transcriptional control of nonclassical target genes. This work broadens our understanding of the Hippo pathway beyond its role in growth control. Citation Format: Heya Zhao, Can Zhang, Kenneth Moberg, Alexey Veraksa. Joint control of epidermal cell fate by Yorkie and Bonus [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B30.

Letrozole Rat Model Mimics Human Polycystic Ovarian Syndrome and Changes in Insulin Signal Pathways.

BackgroundThe aim of this study was to explore whether letrozole and high-fat diets (HFD) can induce obese insulin-resistant polycystic ovary syndrome (PCOS) with all reproductive and metabolic phenotypes in a rat model.Material/MethodsTwenty-four 3-week-old female Sprague-Dawley rats were randomized into 4 groups: control, Letrozole, HFD, and Letrozol+HFD. The PCOS model was induced by 12 weeks of Letrozole treatment (1 mg/kg p.o. dissolved in 0.5% CMC solutions once daily) and HFD. Ovarian morphology, estrous cyclicity, hormonal status, body weight, glucose and insulin tolerance, lipid profile, and insulin signaling pathway were investigated.ResultsThe rat model manifests anovulatory cycles and PCO morphology, increased body weight, elevated testosterone levels, abnormal glucose and lipid metabolism, and insulin resistance. The rat model also expresses significantly decreased phosphorylation of 6 essential signaling proteins – INSR, IRS, PI3K, AKT, ERK1, ERK2 – in the PI3K/AKT and MAPK/ERK pathways in the classic insulin-sensitive tissues (e.g., quadriceps femoris muscle, omentum majus, and liver), as well as non-classic target ovary tissues. Disrupted insulin signaling contributes to the decrease in insulin sensitivity and compensatory hyperinsulinemia in PCOS rats.ConclusionsContinuous administration of letrozole and high-fat diets can induce PCOS, metabolic phenotypes, and disrupted activation of the insulin signaling pathway.

Optimal control of hybrid optomechanical systems for generating non-classical states of mechanical motion

Cavity optomechanical systems are one of the leading experimental platforms for controlling mechanical motion in the quantum regime. We exemplify that the control over cavity optomechanical systems greatly increases by coupling the cavity also to a two-level system, thereby creating a hybrid optomechanical system. If the two-level system can be driven largely independently of the cavity, we show that the nonlinearity thus introduced enables us to steer the extended system to non-classical target states of the mechanical oscillator with Wigner functions exhibiting significant negative regions. We illustrate how to use optimal control techniques beyond the linear regime to drive the hybrid system from the near ground state into a Fock target state of the mechanical oscillator. We base our numerical optimization on realistic experimental parameters for exemplifying how optimal control enables the preparation of decidedly non-classical target states, where naive control schemes fail. Our results thus pave the way for applying the toolbox of optimal control in hybrid optomechanical systems for generating non-classical mechanical states.

Tackling molecular targets beyond PD-1/PD-L1: Novel approaches to boost patients' response to cancer immunotherapy.

In the new era of immunotherapy, which has changed the clinical oncology practice guidelines, there is a pressing need for finding novel approaches to tune up the clinical outcomes of immunotherapy and extend its benefits to a wider cohort of cancer patients. Several non-classical molecular immune targets beyond PD-1/PD-L1 signaling were shown to be engaged as feedback resistance circuits to shut down the antitumor immune response mediated by the classical immune checkpoint inhibitors. Those include T-cell inducible co-stimulator (ICOS), CD40, CD47, V-domain Ig suppressor of T-cell activation (VISTA), cyclin-dependent kinase (CDK)12, enhancer of Zeste homolog 2 (EZH2), toll-like receptors (TLRs) and OX-40 (CD134). Herein we critically discussed the latest studies concerned with understanding the mechanisms involved in the negative clinical response to classical immunotherapies and strategies to optimize the efficacy of cancer immunotherapy through novel combinatorial approaches.

Single-Step Traveling-Wave Quantum State Engineering in the Coherent State Representation

We describe a recently introduced single-step traveling-wave quantum state engineering scheme using the one-dimensional coherent-state representation introduced by Janszky. In this representation, the photon number expansion of the output state is derived in a compact formula that is advantageous for numerical optimization. Using this formula, we determine several sets of physically controllable parameters of the scheme yielding various nonclassical target states.

Primary hyperparathyroidism: recent advances.

The purpose of this review is to describe recent advances and changes in the evaluation and management of primary hyperparathyroidism (PHPT). Although it has long been recognized that asymptomatic PHPT is associated with bone loss, particularly at cortical skeletal sites when evaluated with dual-energy X-ray absorptiometry, new imaging techniques suggest that trabecular skeletal deterioration as well as clinically silent vertebral fractures and nephrolithiasis are common. Nonclassical targets of asymptomatic PHPT as well as the effect of vitamin D deficiency and treatment upon PHPT presentation have been the subject of recent intense investigation. Randomized clinical trials are now available regarding the effect of parathyroidectomy (PTX) upon both classical and nonclassical target organs. They have confirmed results from observational studies with regard to the skeletal benefits of PTX but have not consistently shown improvements in nonclassical symptoms. These findings have led to recommendations for more extensive renal and skeletal evaluation and broader criteria for PTX in PHPT. In addition to dual-energy X-ray absorptiometry, vertebral and renal imaging is recommended. When available, trabecular imaging techniques may be helpful. PTX criteria now include subclinical kidney stones, vertebral fractures and hypercalciuria, in addition to those based on age, serum calcium, bone densitometry and renal function.

Rickets/Osteomalacia. Vitamin D action:Lessons from animal models.

Animal studies using mice model such as vitamin D deficiency and global and conditional VDR knock out(KO)mice have disclosed that the physiological role of vitamin D strongly depends on the calcium balance. Vitamin D stimulates active intestinal calcium transport mechanism, thereby maintains normocalcemia that has priority over skeletal integrity. Besides the biological significance of vitamin D extensively studied, its precise function in non-classical target needs further investigation.

Metabolic Syndrome in Parathyroid Diseases.

Parathyroid glands are the main regulator of body mineral metabolism through parathormone (PTH) actions on bone and kidney. Experimental evidence suggests that PTH may have non-classical target organs such as adipose tissue, arterial vascular wall, cardiac muscle cells, and adrenal cortex cells, where it may play a role in controlling body energy, blood pressure, and metabolism. Cardiometabolic features have been investigated in the wide spectrum of clinical parathyroid disorders, from hyperparathyroidism to pseudohypoparathyroidism and hypoparathyroidism. Indeed, in parathyroid disorders, besides altered PTH secretion, impaired serum calcium levels and vitamin D status occur. Both calcium and vitamin D have been shown to regulate metabolism and to be associated with cardiovascular diseases. However, despite the complexity of parathyroid disorders, features of metabolic syndrome, such as obesity, insulin resistance, and glucose intolerance, arterial blood hypertension, and dyslipidemia, are frequently diagnosed in primary and secondary hyperparathyroidism as well as in pseudohyperparathyroidism. Here, we reviewed the most consistent data highlighting challenges and providing clinical remarks.

Sorafenib Impedes Rift Valley Fever Virus Egress by Inhibiting Valosin-Containing Protein Function in the Cellular Secretory Pathway.

There is an urgent need for therapeutic development to combat infections caused by Rift Valley fever virus (RVFV), which causes devastating disease in both humans and animals. In an effort to repurpose drugs for RVFV treatment, our previous studies screened a library of FDA-approved drugs. The most promising candidate identified was the hepatocellular and renal cell carcinoma drug sorafenib. Mechanism-of-action studies indicated that sorafenib targeted a late stage in virus infection and caused a buildup of virions within cells. In addition, small interfering RNA (siRNA) knockdown studies suggested that nonclassical targets of sorafenib are important for the propagation of RVFV. Here we extend our previous findings to identify the mechanism by which sorafenib inhibits the release of RVFV virions from the cell. Confocal microscopy imaging revealed that glycoprotein Gn colocalizes and accumulates within the endoplasmic reticulum (ER) and the transport of Gn from the Golgi complex to the host cell membrane is reduced. Transmission electron microscopy demonstrated that sorafenib caused virions to be present inside large vacuoles inside the cells. p97/valosin-containing protein (VCP), which is involved in membrane remodeling in the secretory pathway and a known target of sorafenib, was found to be important for RVFV egress. Knockdown of VCP resulted in decreased RVFV replication, reduced Gn Golgi complex localization, and increased Gn ER accumulation. The intracellular accumulation of RVFV virions was also observed in cells transfected with siRNA targeting VCP. Collectively, these data indicate that sorafenib causes a disruption in viral egress by targeting VCP and the secretory pathway, resulting in a buildup of virions within dilated ER vesicles.IMPORTANCE In humans, symptoms of RVFV infection mainly include a self-limiting febrile illness. However, in some cases, infected individuals can also experience hemorrhagic fever, neurological disorders, liver failure, and blindness, which could collectively be lethal. The ability of RVFV to expand geographically outside sub-Saharan Africa is of concern, particularly to the Americas, where native mosquito species are capable of virus transmission. Currently, there are no FDA-approved therapeutics to treat RVFV infection, and thus, there is an urgent need to understand the mechanisms by which the virus hijacks the host cell machinery to replicate. The significance of our research is in identifying the cellular target of sorafenib that inhibits RVFV propagation, so that this information can be used as a tool for the further development of therapeutics used to treat RVFV infection.