Uttroside B, a US-FDA-Designated Orphan Drug Against Hepatocellular Carcinoma (HCC), Impedes Non-alcoholic Steatohepatitis (NASH) and NASH -Induced HCC

Rayginia, T. P.; Keerthana, C. K.; Aiswarya, S. U.; Sadiq, S. C.; S, J.; Varma, S. S.; P, M. J.; Swetha, M.; Retnakumary, A. P.; Nath, L. R.; Kalimuthu, K.; Jaikumar, V. S.; Sundaram, S.; Anto, N. P.; Isakov, N.; Harikumar, K. B.; Lankalapalli, R. S. B.; Anto, R. J.

doi:10.1101/2024.11.06.622394

bioRxiv · 10.1101/2024.11.06.622394

Uttroside B, a US-FDA-Designated Orphan Drug Against Hepatocellular Carcinoma (HCC), Impedes Non-alcoholic Steatohepatitis (NASH) and NASH -Induced HCC

Rayginia, T. P.·Keerthana, C. K.·Aiswarya, S. U.·Sadiq, S. C.·S, J.·Varma, S. S.·P, M. J.·Swetha, M.·Retnakumary, A. P.·Nath, L. R.·Kalimuthu, K.·Jaikumar, V. S.·Sundaram, S.·Anto, N. P.·Isakov, N.·Harikumar, K. B.·Lankalapalli, R. S. B.·Anto, R. J.

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Abstract

IntroductionNon-alcoholic steatohepatitis (NASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury. NASH can lead to chronic conditions like fibrosis and cirrhosis, and has an elevated risk of progressing to hepatocellular carcinoma (HCC). Currently there are no FDA-approved drugs for the treatment of NASH. ObjectivesOur discovery of Uttroside B (Utt-B), a phytosaponin isolated from Solanum nigrum Linn., which exhibits remarkable anti-HCC potential, has gained global recognition and is currently a US-FDA-designated orphan drug against HCC. The present study highlights Utt-B as an anti-NASH molecule, by utilizing a High-Fat-Diet murine model, and as an inhibitor to the progression of NASH to HCC, using a streptozotocin-induced steatohepatitis-derived HCC animal model, thereby warranting its further validation as a propitious candidate drug molecule against NASH and NASH-induced HCC. MethodsHigh fat diet-induced NASH and streptozotocin-induced steatohepatitis-derived HCC were developed in C57BL/6 mice. Utt-B was administered intraperitoneally. q-PCR, immunoblotting and staining techniques such as Haematoxylin and eosin, Oil Red O, Sirius Red and Massons Trichrome, were performed to assess the therapeutic potency of Utt-B against NASH. Nanostring n-Counter analysis was conducted to verify the anti-fibrotic potential of Utt-B in NASH-induced HCC mouse model. ResultsUtt-B ameliorates the pathological features such as, steatosis, hepatocyte ballooning and inflammation associated with NASH. Utt-B up-regulates the expression of autophagy markers ATG7, Beclin-1 and LC-III and down-regulates the expression of -SMA, the indicator protein for the activation of hepatic stellate cells. Utt-B hinders the development of fibrosis and halts the progression of NASH to HCC in NASH-induced HCC mouse model. ConclusionOur investigation reveals that Utt-B effectively alleviates NASH and abrogates its progression to HCC. As no treatment options are currently available against NASH, our findings are very relevant and strengthen the prospect of developing Utt-B as a potent drug for the treatment of NASH and NASH-induced HCC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/622394v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1d637dcorg.highwire.dtl.DTLVardef@ed6b34org.highwire.dtl.DTLVardef@1195acaorg.highwire.dtl.DTLVardef@197b072_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Rayginia, T. P., Keerthana, C. K., Aiswarya, S. U., Sadiq, S. C., S, J., Varma, S. S., P, M. J., Swetha, M., Retnakumary, A. P., Nath, L. R., Kalimuthu, K., Jaikumar, V. S., Sundaram, S., Anto, N. P., Isakov, N., Harikumar, K. B., Lankalapalli, R. S. B., Anto, R. J.. 2024-11-08. Uttroside B, a US-FDA-Designated Orphan Drug Against Hepatocellular Carcinoma (HCC), Impedes Non-alcoholic Steatohepatitis (NASH) and NASH -Induced HCC. https://doi.org/10.1101/2024.11.06.622394

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