AUTHOR=Sarcognato Samantha , Sacchi Diana , Fabris Luca , Zanus Giacomo , Gringeri Enrico , Niero Monia , Gallina Giovanna , Guido Maria 

TITLE=Ferroptosis in Intrahepatic Cholangiocarcinoma: IDH1105GGT Single Nucleotide Polymorphism Is Associated With Its Activation and Better Prognosis

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.886229

DOI=10.3389/fmed.2022.886229

ISSN=2296-858X

ABSTRACT=<sec><title>Objectives</title><p>Intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis and often demonstrates an anti-apoptotic landscape, which is a key step to chemotherapy resistance. Isocitrate dehydrogenase 1 or 2 (<italic>IDH1-2</italic>)-mutated ICCs have been described and associated with better prognosis. Ferroptosis is a regulated iron-mediated cell death induced by glutathione peroxidase 4 (GPX4) inhibition, and may be triggered pharmacologically. GPX4 is overexpressed in aggressive cancers, while its expression is inhibited by <italic>IDH1</italic><sup><italic>R</italic>132<italic>C</italic></sup> mutation in cell lines. We investigated tissue expression of ferroptosis activation markers in ICC and its correlation with clinical-pathological features and <italic>IDH1-2</italic> status.</p></sec><sec><title>Materials and Methods</title><p>We enrolled 112 patients who underwent hepatic resection or diagnostic liver biopsy for ICC. Immunostaining for transferrin-receptor 1 and GPX4, and Pearls’ stain for iron deposits were performed to evaluate ferroptosis activation. Immunostaining for STAT3 was performed to study pro-inflammatory and anti-apoptotic landscape. Main <italic>IDH1-2</italic> mutations were investigated in 90 cases by real-time polymerase chain reaction.</p></sec><sec><title>Results</title><p>GPX4 overexpression was seen in 79.5% of cases and related to poor histological prognostic factors (grading and perineural and vascular invasion; <italic>p</italic> &lt; 0.005 for all) and worse prognosis (OS <italic>p</italic> = 0.03; DFS <italic>p</italic> = 0.01). STAT3 was expressed in 95.5% of cases, confirming the inflammation-related anti-apoptotic milieu in ICC, and directly related to GPX4 expression (<italic>p</italic> &lt; 0.0001). A high STAT3 expression correlated to a worse prognosis (OS <italic>p</italic> = 0.02; DFS <italic>p</italic> = 0.001). Nearly 12% of cases showed <italic>IDH1</italic><sup>105<italic>GGT</italic></sup> single nucleotide polymorphism, which was never described in ICC up to now, and was related to lower tumor grade (<italic>p</italic> &lt; 0.0001), longer overall survival (<italic>p</italic> = 0.04), and lower GPX4 levels (<italic>p</italic> = 0.001).</p></sec><sec><title>Conclusion</title><p>Our study demonstrates for the first time that in most inflammatory ICCs ferroptosis is not active, and its triggering is related to <italic>IDH1-2</italic> status. This supports the possible therapeutic role of ferroptosis-inducer drugs in ICC patients, especially in drug-resistant cases.</p></sec>