Curcumol alleviates liver fibrosis through inducing autophagy and ferroptosis in hepatic stellate cells

Abstract

To explore the effect of curcumol on autophagy and ferroptosis of hepatic stellate cells, and to clarify the molecular mechanism of its anti-hepatic fibrosis. In the present study, we report that curcumol promotes the death of activated HSCs and reduces the deposition of extracellular matrix. Interestingly, curcumol treatment can trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation.Curcumol promotes HSC autophagy, which may be the key mechanism for its induction of ferroptosis. It is worth noting that the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a key molecular mechanism. NCOA4 mediates the release of iron ions and induces the occurrence of ferroptosis. Overall, curcumol promotes autophagy in hepatic stellate cells, mediates the degradation of NCOA4 and FTH1 complexes, releases iron ions, leads to iron overload, and induces ferroptosis, which may be an important mechanism for its anti-hepatic fibrosis effect.

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

“…It can induce both the autophagy and apoptosis of hepatic stellate cells. Since fibrosis is an important factor for the initiation of HCC, this dual action of curcumol may favorably influence HCC initiation [ 311 ]. However, a detrimental outcome may be the result of the concerted action of apoptosis and autophagy.…”

Pharmacological modulation of ferroptosis as a therapeutic target for liver fibrosis

“…Mounting evidence from in vitro and in vivo models indicates that pharmacological induction of ferroptosis may mitigate liver fibrosis development ( Table 1 ). Moreover, there is an increasing body of evidence showing that inducing HSCs ferroptosis using Curcumol ( Zheng et al, 2022 ), ellagic acid ( Li et al, 2022 ), phloridzin ( Shi et al, 2022 ), liraglutide ( Song et al, 2022 ), berberine ( Yi et al, 2021 ), wogonoside ( Liu et al, 2022 ), decursin ( Que et al, 2022 ), celastrol ( Luo et al, 2022 ),isoliquiritigenin ( Huang et al, 2022 ), DHA ( Zhang et al, 2021 ; Shen et al, 2022 ), wild bitter melon extract (WBME) ( Ho et al, 2021 ),chrysophanol ( Kuo et al, 2020 ), magnesium isoglycyrrhizinate ( Sui et al, 2018 ), artesunate ( Kong et al, 2019 ), and artemether ( Wang et al, 2019 ) has potential as a therapeutic strategy to prevent or inhibit liver fibrosis. Curcumol ( Zheng et al, 2022 ), ellagic acid ( Li et al, 2022 ), wogonoside ( Liu et al, 2022 ), decursin, sorafenib, berberine, celastrol ( Luo et al, 2022 ), isoliquiritigenin ( Huang et al, 2022 ), DHA ( Zhang et al, 2021 ), WBME ( Ho et al, 2021 ), and chrysophanol ( Kuo et al, 2020 ) alleviate liver fibrosis through inducing ferroptosis by inhibiting SLC7A11.…”

“…Curcumol ( Zheng et al, 2022 ), ellagic acid ( Li et al, 2022 ), wogonoside ( Liu et al, 2022 ), decursin, sorafenib, berberine, celastrol ( Luo et al, 2022 ), isoliquiritigenin ( Huang et al, 2022 ), DHA ( Zhang et al, 2021 ), WBME ( Ho et al, 2021 ), and chrysophanol ( Kuo et al, 2020 ) alleviate liver fibrosis through inducing ferroptosis by inhibiting SLC7A11. Curcumol inhibits GPX4, thereby inducing HSCs ferroptosis to alleviate liver fibrosis ( Zheng et al, 2022 ). Isoliquiritigenin inhibits DHODH and upregulates POR, thereby inducing ferroptosis to alleviate liver fibrosis ( Sui et al, 2018 ).…”

“…Artesunate ( Kong et al, 2019 ) and DHA ( Zhang et al, 2021 ) induces NCOA4-mediated ferritinophagy to induce ferroptosis and alleviate liver fibrosis. Curcumol ( Zheng et al, 2022 ) and DHA ( Zhang et al, 2021 ) induced ACSL4-dependant ferroptosis to alleviate liver fibrosis. Berberine ( Yi et al, 2021 ) and curcumol ( Zheng et al, 2022 ) alleviate liver fibrosis through inhibiting FTH1/FTL.…”

“…Curcumol ( Zheng et al, 2022 ) and DHA ( Zhang et al, 2021 ) induced ACSL4-dependant ferroptosis to alleviate liver fibrosis. Berberine ( Yi et al, 2021 ) and curcumol ( Zheng et al, 2022 ) alleviate liver fibrosis through inhibiting FTH1/FTL. Ellagic acid ( Li et al, 2022 ) and MgIG ( Sui et al, 2018 ) downregulates FPN1 to induce ferroptosis and alleviate liver fibrosis.…”