*2.3. Therapeutic Strategies Targeting Ubls Modifications in Liver Fibrosis*

As a result of several studies in the last decades about the role of PTMs, specifically Ubl-mediated protein modifications, and their implication in disease, many therapeutic agents targeting these modifications have been developed lately (see Reviews [84–87]). Nevertheless, only a small fraction of these agents was tested in liver fibrosis.

Regarding ubiquitination, the role of the pharmacological inhibitor LDN 57444, an inhibitor of the deubiquitinase ubiquitin C-terminal hydrolase1 (UCHL1), was also evaluated and shown to block the progression of established fibrosis in the carbon tetrachloride (CCl4) injured mice [37]. In addition, Indole-3-carbinol (I3C), a naturally occurring compound generated from the hydrolysis of glucobrassicin and found in high concentrations in *Brassica* vegetables, was shown to induce apoptosis of HSC through RIP1 K63 de-ubiquitination by upregulating deubiquitinase CYLD [88].

Therapeutic strategies targeting NEDDylation in liver fibrosis have also been evaluated. As it was previously mentioned, pre-clinical studies in mouse models have shown that the small pharmacological inhibitor of NEDDylation, Pevonedistat, or MLN4924 [89], is able to revert liver fibrosis [61]. Pevonedistat (MLN4924) is a potent and selective NAE1 inhibitor that is currently undergoing several clinical trials to treat some leukemias and some types of solid organ cancer pathologies. Taking this into account, translation of Pevonedistat from pre-clinical mouse models to clinical trials for liver fibrosis treatment should be a fast process. Finally, to our knowledge, the role of the inhibition of the SUMOylation pathway or specific enzymes of this pathway in liver fibrosis has not been assessed to date.
