Reply.

Abstract

Potential conflict of interest: Nothing to report. Reply: Chen et al. propose a further loop to the IL‐6/STAT3–mIndy axis1 by recalling that interleukin‐6 (IL‐6) is an important player in chronic inflammation–related hepatocellular carcinoma (HCC). Moreover, excellent work in human hepatoma cell lines showed that RNAi‐mediated knockdown of the citrate transporter mINDY was associated with a decrease in cell proliferation, colony formation, and expression of cyclin B1. Metabolically, intracellular levels of citrate, the ATP/ADP ratio, phospholipid content, ATP citrate lyase expression, and mTOR activity decreased, whereas AMPK was activated,2 validating the effect of mIndy deletion in vivo.3 We do not know whether the findings in mice, human hepatoma cell lines, and human liver samples translate into chronic, physiologically significant effects in patients with HCC. Presumably, however, IL‐6 contributes to HCC development together with a complex molecular network, including phospholipids, citrate, AMPK, and mTOR. This part of the argument by Chen et al., therefore, is pertinent and plausible. It is thus reassuring that small molecule inhibitors of mINDY are available,4 because they may serve as interesting tools for the study of mIndy and citrate in hepatic tumorigenesis. Moreover, according to the data discussed above, inhibition of mINDY may hold the potential to be effective in the treatment of HCC; however, this notion needs to be studied further. Thus far, pharmacological inhibition of mINDY has been shown to be effective in improving glucose tolerance and reducing liver fat in diet‐induced obese mice,4 effects that also protect against HCC.