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Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA‐mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib‐induced ferroptosis. Mechanistically, in a TEAD‐dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib‐induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ‐based rewiring strategies as potential approaches to overcome HCC therapy resistance. SYNOPSIS Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib. The transcription factors YAP and TAZ stabilize ATF4 by promoting its nuclear import to cooperatively induce expression of SLC7A11, a cystine importer critical for glutathione synthesis. Glutathione synthesis and homeostasis are required to repress ferroptosis and to maintain Sorafenib resistance in liver cancer cells. Inhibition of Glutathione synthesis re‐sensitizes Sorafenib‐resistant cancer cells to Sorafenib therapy, which then induces ferroptosis and represses tumor growth in murine liver cancer models. Pharmacological repression of the anti‐oxidant pathways regulated by YAP/TAZ and ATF4 could re‐sensitize therapy‐resistant liver cancers to Sorafenib treatment. Graphical Abstract Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.

Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D 2 . However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD 2 production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro‐inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro‐inflammatory gene expression of macrophages. Moreover, treatment with niacin‐containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS‐induced colitis in mice by activation of PGD 2 /DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation. Synopsis Niacin, an ancient lipid‐lowering drug that elicits a strong flushing response through release of prostaglandin (PG) D 2 . Niacin improves experimentally induced ulcerative colitis in mice and humans through the activation of PGD 2 /DP1 axis. Niacin increases PGD 2 release in both mice and humans. Niacin confers protection against DSS/TNBS‐induced colitis in mice through DP1‐mediated inhibition of vascular leakage, suppression of colonic epithelium apoptosis, and reduction of pro‐inflammatory cytokine secretion. Retention enema treatment containing niacin effectively promotes clinical remission and mucosal healing in patients with moderately active UC. Graphical Abstract Niacin, an ancient lipid‐lowering drug that elicits a strong flushing response through release of prostaglandin (PG) D 2 . Niacin improves experimentally induced ulcerative colitis in mice and humans through the activation of PGD 2 /DP1 axis.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of cardiometabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. It is rapidly becoming the most prevalent liver disease worldwide. A sizable minority of NAFLD patients develop nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, cirrhosis, and hepatocellular carcinoma. Recent studies have shown that in addition to genetic predisposition and diet, the gut microbiota affects hepatic carbohydrate and lipid metabolism as well as influences the balance between pro‐inflammatory and anti‐inflammatory effectors in the liver, thereby impacting NAFLD and its progression to NASH. In this review, we will explore the impact of gut microbiota and microbiota‐derived compounds on the development and progression of NAFLD and NASH, and the unexplored factors related to potential microbiome contributions to this common liver disease. Graphical Abstract In this review, Kolodziejczyk, Elinav and colleagues explore the impact that the gut microbiota may have on the development and progression of nonalcoholic liver diseases (i.e. NAFLD and NASH), and discuss the unexplored factors related to potential microbiome contributions to this common disorder.

In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define transcriptional states of colorectal cancer cells and signals controlling their development by performing single‐cell transcriptome analysis of tumors and matched non‐cancerous tissues of twelve colorectal cancer patients. We defined patient‐overarching colorectal cancer cell clusters characterized by differential activities of oncogenic signaling pathways such as mitogen‐activated protein kinase and oncogenic traits such as replication stress. RNA metabolic labeling and assessment of RNA velocity in patient‐derived organoids revealed developmental trajectories of colorectal cancer cells organized along a mitogen‐activated protein kinase activity gradient. This was in contrast to normal colon organoid cells developing along graded Wnt activity. Experimental targeting of EGFR‐BRAF‐MEK in cancer organoids affected signaling and gene expression contingent on predictive KRAS/BRAF mutations and induced cell plasticity overriding default developmental trajectories. Our results highlight directional cancer cell development as a driver of non‐genetic cancer cell heterogeneity and re‐routing of trajectories as a response to targeted therapy. SYNOPSIS Colorectal cancer (CRC) cells can adopt a range of transcriptomic states. This study uses single cell RNA sequencing of primary CRC tissue and organoids to identify patient‐overarching CRC cell transcriptome clusters. RNA metabolic labelling indicates preferred CRC cell developmental trajectories. CRC cells of multiple patients clustered into six groups – termed TC1‐4, Goblet‐like, and stem‐like – characterized by differential transcriptional footprints of oncogenic signaling pathways. CRC organoid cells develop along a decreasing MAPK gradient. Experimental targeting of EGFR‐MAPK in CRC organoids re‐routes developmental trajectories. Clinically relevant inhibition of EGFR‐MAPK can result in preferential CRC cell development towards endpoints expressing high levels of stem cell markers. Graphical Abstract Colorectal cancer (CRC) cells can adopt a range of transcriptomic states. This study uses single cell RNA sequencing of primary CRC tissue and organoids to identify patient‐overarching CRC cell transcriptome clusters. RNA metabolic labelling indicates preferred CRC cell developmental trajectories.

Paneth cells are versatile secretory cells located in the crypts of Lieberkühn of the small intestine. In normal conditions, they function as the cornerstones of intestinal health by preserving homeostasis. They perform this function by providing niche factors to the intestinal stem cell compartment, regulating the composition of the microbiome through the production and secretion of antimicrobial peptides, performing phagocytosis and efferocytosis, taking up heavy metals, and preserving barrier integrity. Disturbances in one or more of these functions can lead to intestinal as well as systemic inflammatory and infectious diseases. This review discusses the multiple functions of Paneth cells, and the mechanisms and consequences of Paneth cell dysfunction. It also provides an overview of the tools available for studying Paneth cells. Graphical Abstract This Review discusses biological functions of Paneth cells and their importance for intestinal homeostasis and organismal health.

Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4 + effector T cells producing IL‐17A and TNF, CD8 + T cells producing IFNγ, T regulatory (Treg) cells, and innate lymphoid cells (ILC). The function of these immune cells is regulated by store‐operated Ca 2+ entry (SOCE), which results from the opening of Ca 2+ release‐activated Ca 2+ (CRAC) channels formed by ORAI and STIM proteins. We observed that the pharmacologic inhibition of SOCE attenuated the production of proinflammatory cytokines including IL‐2, IL‐4, IL‐6, IL‐17A, TNF, and IFNγ by human colonic T cells and ILCs, reduced the production of IL‐6 by B cells and the production of IFNγ by myeloid cells, but had no effect on the viability, differentiation, and function of intestinal epithelial cells. T cell‐specific deletion of CRAC channel genes in mice showed that Orai1 , Stim1 , and Stim2 ‐deficient T cells have quantitatively distinct defects in SOCE, which correlate with gradually more pronounced impairment of cytokine production by Th1 and Th17 cells and the severity of IBD. Moreover, the pharmacologic inhibition of SOCE with a selective CRAC channel inhibitor attenuated IBD severity and colitogenic T cell function in mice. Our data indicate that SOCE inhibition may be a suitable new approach for the treatment of IBD. Synopsis The immune cell composition, signaling cascades, and cytokine networks controlling inflammation in therapy‐refractory inflammatory bowel diseases (IBD) remain incompletely understood. The colon lamina propria (LP) of ulcerative colitis (UC) and Crohn's disease (CD) patients is enriched with CD4 + and CD8 + T cells, IL‐17‐producing innate immune cells (ILC) and Treg cells. Pharmacological inhibition of store‐operated Ca 2+ Entry (SOCE) inhibits the production of proinflammatory cytokines and certain activation markers by human LP T cells, B cells, ILCs and myeloid cells. Inhibition of SOCE does not impair the differentiation and function of human or mouse intestinal epithelial cells in colonic organoid cultures. Pharmacologic inhibition of SOCE or T cell‐specific deletion of the SOCE genes Orai1 and Stim1 in T cells ameliorates intestinal inflammation in mouse models of colitis. SOCE is an important regulator of intestinal immune cell function and a potential drug target for the treatment of IBD. Graphical Abstract The immune cell composition, signaling cascades, and cytokine networks controlling inflammation in therapy‐refractory inflammatory bowel diseases (IBD) remain incompletely understood.

Severe radiation exposure may cause acute radiation syndrome, a possibly fatal condition requiring effective therapy. Gut microbiota can be manipulated to fight against many diseases. We explored whether intestinal microbe transplantation could alleviate radiation‐induced toxicity. High‐throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Faecal microbiota transplantation (FMT) increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improved gastrointestinal tract function and intestinal epithelial integrity in irradiated male and female mice. FMT preserved the intestinal bacterial composition and retained mRNA and long non‐coding RNA expression profiles of host small intestines in a sex‐specific fashion. Despite promoting angiogenesis, sex‐matched FMT did not accelerate the proliferation of cancer cells in vivo . FMT might serve as a therapeutic to mitigate radiation‐induced toxicity and improve the prognosis of tumour patients after radiotherapy. Synopsis Faecal microbiota transplantation ameliorates radiation‐induced toxicity in irradiated mice by improving gastrointestinal tract function and epithelial integrity, preserving gut bacterial composition and maintaining the small intestine transcriptome. Gut microbiota determines the radiosensitivity of hosts. Faecal microbiota transplantation (FMT) fights against radiation‐induced gastrointestinal toxicity. FMT preserves enteric bacterial composition and retains the RNA expression profile of irradiated hosts. FMT might emerge as a therapeutic schedule in tumour radiotherapy to improve prognosis. Graphical Abstract Faecal microbiota transplantation ameliorates radiation‐induced toxicity in irradiated mice by improving gastrointestinal tract function and epithelial integrity, preserving gut bacterial composition and maintaining the small intestine transcriptome.

Non‐alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non‐alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell death—so far characterized as hepatocyte apoptosis—represents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3‐dependent “necroptosis” in NASH and NASH‐induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase‐8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun‐(N)‐terminal Kinase (JNK). Furthermore, RIP3‐dependent JNK activation promotes the release of pro‐inflammatory mediators like MCP‐1, thereby attracting macrophages to the injured liver and further augmenting RIP3‐dependent signaling, cell death, and liver fibrosis. Thus, RIP3‐dependent necroptosis controls NASH‐induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH. Synopsis RIP3‐dependent necroptosis mediates NASH‐induced liver fibrosis via activation of JNK, MCP‐1‐mediated recruitment of monocytes, and an expansion of intrahepatic biliary/progenitor cells. Caspase‐8 appears to suppress the deleterious effect of RIP3. RIP3 mediates liver injury in MCD‐diet‐induced NASH. RIP3—similar to Caspase‐8—does not affect CCl4‐induced liver fibrosis and thus might be a specific target in metabolic liver disease. Human NASH livers strongly express RIP3. Targeting RIP3 might represent a novel‐specific approach in human NASH. Graphical Abstract RIP3‐dependent necroptosis mediates NASH‐induced liver fibrosis via activation of JNK, MCP‐1‐mediated recruitment of monocytes, and an expansion of intrahepatic biliary/progenitor cells. Caspase‐8 appears to suppress the deleterious effect of RIP3.

Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage‐mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3‐associated phagocytosis (LAP), a non‐canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G‐protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL‐induced efferocytosis, anti‐colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3‐associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease. Synopsis Enhancement of efferocytosis has been regarded as an emerging strategy for inflammatory diseases, while pharmacological approaches to modulate efferocytosis are poorly defined. Our study identified a natural compound, columbamine (COL), that can activate LC3‐associated efferocytosis and attenuate DSS‐induced colitis by biasedly targeting FPR2 on macrophages. This study provides a novel therapeutic strategy for inflammatory diseases, including colitis, via enhancing FPR2‐mediated efferocytosis. COL has been identified as a novel efferocytosis enhancer that ameliorates mouse colitis. COL binds to and biasedly activates FPR2, leading to enhanced efferocytosis in macrophages. FPR2 emerges as a promising therapeutic target for the treatment of inflammatory diseases through modulating LC3‐associated efferocytosis in macrophages. Graphical Abstract Enhancement of efferocytosis has been regarded as an emerging strategy for inflammatory diseases, while pharmacological approaches to modulate efferocytosis are poorly defined. Our study identified a natural compound, columbamine (COL), that can activate LC3‐associated efferocytosis and attenuate DSS‐induced colitis by biasedly targeting FPR2 on macrophages. This study provides a novel therapeutic strategy for inflammatory diseases, including colitis, via enhancing FPR2‐mediated efferocytosis.

Enteric glial cells (EGC) modulate motility, maintain gut homeostasis, and contribute to neuroinflammation in intestinal diseases and motility disorders. Damage induces a reactive glial phenotype known as “gliosis”, but the molecular identity of the inducing mechanism and triggers of “enteric gliosis” are poorly understood. We tested the hypothesis that surgical trauma during intestinal surgery triggers ATP release that drives enteric gliosis and inflammation leading to impaired motility in postoperative ileus (POI). ATP activation of a p38‐dependent MAPK pathway triggers cytokine release and a gliosis phenotype in murine (and human) EGCs. Receptor antagonism and genetic depletion studies revealed P2X2 as the relevant ATP receptor and pharmacological screenings identified ambroxol as a novel P2X2 antagonist. Ambroxol prevented ATP‐induced enteric gliosis, inflammation, and protected against dysmotility, while abrogating enteric gliosis in human intestine exposed to surgical trauma. We identified a novel pathogenic P2X2‐dependent pathway of ATP‐induced enteric gliosis, inflammation and dysmotility in humans and mice. Interventions that block enteric glial P2X2 receptors during trauma may represent a novel therapy in treating POI and immune‐driven intestinal motility disorders. Synopsis Enteric gliosis was shown to be part of an intestinal immune response upon abdominal surgery. ATP activates enteric glial cells via selective purinergic receptor signalling in mice and humans. Inhibition of this pathogenic pathway by the newly identified P2X2 antagonist ambroxol blocks ATP‐induced enteric gliosis and protects against postoperative ileus. Reactive enteric glia actively contribute to intestinal neuroinflammation and disruption of motility in intestinal disorders and GI diseases. ATP induces a gliosis phenotype in enteric glia as occurs in postoperative ileus. ATP triggers P2X2‐signaling to promote enteric gliosis and inflammation contributing to disruption of motility in the mouse and human gut. P2X2 antagonism with a newly identified P2X2 antagonist drug ambroxol reduces gliosis and improves clinical symptoms of postoperative bowel inflammation. Graphical Abstract Enteric gliosis was shown to be part of an intestinal immune response upon abdominal surgery. ATP activates enteric glial cells via selective purinergic receptor signalling in mice and humans. Inhibition of this pathogenic pathway by the newly identified P2X2 antagonist ambroxol blocks ATP‐induced enteric gliosis and protects against postoperative ileus.