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◥KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here, we report that p38g MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38g interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38g increased expression of PFKFB3 and glucose transporter GLUT2, conversely, silencing mutant KRAS, and p38g decreased PFKFB3 and GLUT2 expression. p38g phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout of p38g decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38g to stimulate glycolysis and PDAC growth and p38g required PFKFB3/S467 to promote these activities. A p38g inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38g. Moreover, overexpression of p38g, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38g links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38g and PFKFB3 may be targeted for therapeutic intervention in PDAC.Significance: These findings show that p38g links KRAS oncogene signaling and the Warburg effect through PFKBF3 and Glut2 to promote pancreatic tumorigenesis, which can be disrupted via inhibition of p38g and PFKFB3.

The purpose of this editorial is to distinguish between case reports and case studies. In health, case reports are familiar ways of sharing events or efforts of intervening with single patients with previously unreported features. As a qualitative methodology, case study research encompasses a great deal more complexity than a typical case report and often incorporates multiple streams of data combined in creative ways. The depth and richness of case study description helps readers understand the case and whether findings might be applicable beyond that setting.

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Context.— Fatty liver disease is now one of the most commonly encountered entities in the practice of liver pathology. Distinguishing simple steatosis from steatohepatitis is critical because the latter requires follow-up because of long-term risks that include cirrhosis and hepatocellular carcinoma. An organized approach for evaluating liver biopsies with steatosis is recommended to capture all of the relevant features: (1) degree of steatosis, (2) presence or absence of ballooning degeneration, (3) lobular inflammation, and (4) fibrosis. Herein, we provide a stepwise approach that readers can use to evaluate liver biopsies with steatosis, including examples, pitfalls, differential diagnostic considerations, and suggested diagnostic phrasing. Objective.— To provide a stepwise approach for the evaluation of liver biopsies showing significant steatosis (involving ≥5% of liver parenchyma). Data Sources.— Biopsies demonstrating fatty liver disease encountered in our daily practice were examined as well as recent literature. Conclusions.— Effective evaluation of liver biopsies with steatosis requires careful histologic examination and correlation with clinical history, particularly regarding medications, nutrition status, and alcohol use. Examples of uniform reporting, including appropriate use of the nonalcoholic steatohepatitis Clinical Research Network Activity Score, are provided.