Role of liensinine in sensitivity of activated macrophages to ferroptosis and in acute liver injury

Abstract

Acute liver injury (ALI) is an acute inflammatory liver disease with a high mortality rate. Alternatively, activated macrophages (AAMs) have been linked to the inflammation and recovery of ALI. However, the mechanism underlying AAM death in ALI has not been studied sufficiently. We used liensinine (Lie) as a drug of choice after screening a library of small-molecule monomers with 1488 compounds from traditional Chinese remedies. In ALI, we evaluated the potential therapeutic effects and underlying mechanisms of action of the drug in ALI and found that it effectively inhibited RSL3-induced ferroptosis in AAM. Lie significantly reduced lipid peroxidation in RSL3-generated AAM. It also improved the survival rate of LPS/D-GalN-treated mice, reduced serum transaminase activity, suppressed inflammatory factor production, and may have lowered AAM ferroptosis in ALI. Lie also inhibited ferritinophagy and blocked Fe2+ synthesis. Following combined treatment with RSL3 and Lie, super-resolution microscopy revealed a close correlation between ferritin and LC3-positive vesicles in the AAM. The co-localization of ferritin and LC3 with LAMP1 was significantly reduced. These findings suggest that Lie may ameliorate ALI by inhibiting ferritinophagy and enhancing AMM resistance to ferroptosis by inhibiting autophagosome-lysosome fusion. Therefore, Lie may be used as a potential therapeutic agent for patients with ALI.

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

“…TCM and its derivatives have shown great therapeutic potential for ALI. Although the mechanisms are not exactly the same, ginsenoside Rd [100], bicyclol [101], gandankang [102], sulforaphane [83], genipin [53], baicalein [103], liensinine [104],…”

“…TCM and its derivatives have shown great therapeutic potential for ALI. Although the mechanisms are not exactly the same, ginsenoside Rd [ 100 ], bicyclol [ 101 ], gandankang [ 102 ], sulforaphane [ 83 ], genipin [ 53 ], baicalein [ 103 ], liensinine [ 104 ], artemisitene [ 105 ], glycyrrhizin [ 106 ], niujiaodihuang detoxify decoction [ 107 ], and low-polarity fraction from Ficus pandurata Hance [ 108 ] have all been shown to alleviate CCl-4 or LPS/ D-gal-induced ALI via preventing ferroptosis. NRF2, GPX4, and lipid metabolism-related enzymes such as ALOX12/15 and ACSL4 are the major targets of these TCMs.…”

Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy

“…The relationship between autophagy and ferroptosis is well-established. mTOR, an autophagy inhibitor, also inhibits ferroptosis by regulating GPX4 synthesis [ 56 ], while liensinine protects against acute lung injury by enhancing M2 macrophage resistance to ferroptosis through autophagy regulation [ 57 ]. Interestingly, both pyroptosis and autophagy promote ferroptosis, but not each other, exhibiting an antagonistic relationship.…”

“…M2-type macrophages, known for their role in inflammation and recovery from ALI [ 57 ], may be susceptible to ferroptosis, potentially affecting survival and liver function in LPS/GalN-induced ALI. Investigating the potential therapeutic effects and mechanisms of action of liensinine in ALI, researchers observed an increased survival rate and reduced inflammatory factor production in LPS/GalN-treated mice treated with liensinine.…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“… 435 Various hepatotoxic factors, including lipid deposition, viruses, and drugs, can induce ALI. Emerging studies have suggested that ferroptosis plays a role in the genesis of ALI 436 – 444 and have revealed the roles of epigenetic regulation of ferroptosis by ubiquitination in ALI 410 – 415 (Table 10 ). Mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exos) alleviate injury through ferroptosis inhibition by decreasing the mRNA levels of Ptgs2 and LOXs while increasing the protein level of SLC7A11 in CCl 4 -induced ALI.…”