Novel role for epalrestat: protecting against NLRP3 inflammasome-driven NASH by targeting aldose reductase

Abstract

Background Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury, inflammation, and fibrosis in various stages. More than 20% of patients with NASH will progress to cirrhosis. Currently, there is a lack of clinically effective drugs for treating NASH, as improving liver histology in NASH is difficult to achieve and maintain through weight loss alone. Hence, the present study aimed to investigate potential therapeutic drugs for NASH. Methods BMDMs and THP1 cells were used to construct an inflammasome activation model, and then we evaluated the effect of epalrestat on the NLRP3 inflammasome activation. Western blot, real-time qPCR, flow cytometry, and ELISA were used to evaluate the mechanism of epalrestat on NLRP3 inflammasome activation. Next, MCD-induced NASH models were used to evaluate the therapeutic effects of epalrestat in vivo. In addition, to evaluate the safety of epalrestat in vivo, mice were gavaged with epalrestat daily for 14 days. Results Epalrestat, a clinically effective and safe drug, inhibits NLRP3 inflammasome activation by acting upstream of caspase-1 and inducing ASC oligomerization. Importantly, epalrestat exerts its inhibitory effect on NLRP3 inflammasome activation by inhibiting the activation of aldose reductase. Further investigation revealed that the administration of epalrestat inhibited NLRP3 inflammasome activation in vivo, alleviating liver inflammation and improving NASH pathology. Conclusions Our study indicated that epalrestat, an aldose reductase inhibitor, effectively suppressed NLRP3 inflammasome activation in vivo and in vitro and might be a new therapeutic approach for NASH. Graphical Abstract

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

“…We decided to explore targeting the NLRP3 inflammasome with an inhibitor to attempt to rescue the increased susceptibility of BD COs. Currently, MCC950 is the leading compound used to inhibit the NLRP3 activation, however it has been implicated with hepatotoxicity 49,50 . Our group has previously published on the use of a BFE, derived from Euterpe oleracea Mart.…”

“…This drug has been widely considered as an anti-inflammatory alternative to treat NLRP3 induced inflammation, including in autoinflammatory and autoimmune diseases 77 . However growing concerns over hepatotoxicity of MCC950 in phase II clinical trials underlines the need for alternatives 49,50 .…”

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

“…We decided to explore targeting the NLRP3 inflammasome with an inhibitor to attempt to rescue the increased susceptibility of BD COs. Currently, MCC950 is the leading compound used to inhibit the NLRP3 activation, however it has been implicated with hepatotoxicity 49,50 . Our group has previously published on the use of a BFE, derived from Euterpe oleracea Mart.…”

“…This drug has been widely considered as an anti-inflammatory alternative to treat NLRP3 induced inflammation, including in autoinflammatory and autoimmune diseases 77 . However growing concerns over hepatotoxicity of MCC950 in phase II clinical trials underlines the need for alternatives 49,50 .…”

Metabolic and Vascular Inflammation in Alopecia Areata: Linking Uric Acid, Lipid Imbalance and ICAM ‐1 Upregulation

“…UA upregulates the polyol pathway, likely through oxidative stress‐induced NFAT5 activation and AKR1B1 activation [ 21 ]. Endogenous fructose production occurs in other tissues such as the liver [ 58 ], and the impact of UA‐polyol pathway interplay on liver disease and endothelial damage is well documented [ 21 , 40 , 41 , 59 , 60 ], and both UA and the polyol pathway are known to mediate activation of the NLRP3 inflammasome [ 61 , 62 ]. In HFs, endogenous fructose may be utilised via GLUT5 and other fructose transporters to promote the Warburg effect to sustain hair growth [ 14 , 63 ].…”

Updated mechanisms of MASLD pathogenesis

“…Various caspase inhibitors (Q-VD-OPh, Belnacasan/VX765) have been pioneered, offering candidate therapeutic strategies for MASLD [ 60 , 61 ]. An aldose reductase inhibitor, epalrestat, acts as the upstream of caspase-1 to inhibit NLRP3 inflammatory vesicles and ameliorate MASH pathology [ 62 ]. Recently, Elodie Bosc et al presented a definitive perspective on caspase-2-specific inhibitors for the treatment of MASLD, while their studies exposed that 3-(S)-neopentyl proline (LJ3a) and 6-methyl-tetrahydro-isoquinoline (LJ2a) inhibited caspase-2-mediated activation of SREBP2 [ 63 ].…”

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

“…We decided to explore targeting the NLRP3 inflammasome with an inhibitor to attempt to rescue the increased susceptibility of BD COs. Currently, MCC950 is the leading compound used to inhibit the NLRP3 activation, however it has been implicated with hepatotoxicity 49,50 . Our group has previously published on the use of a BFE, derived from Euterpe oleracea Mart.…”

“…This drug has been widely considered as an anti-inflammatory alternative to treat NLRP3 induced inflammation, including in autoinflammatory and autoimmune diseases 77 . However growing concerns over hepatotoxicity of MCC950 in phase II clinical trials underlines the need for alternatives 49,50 .…”

Metabolic and Vascular Inflammation in Alopecia Areata: Linking Uric Acid, Lipid Imbalance and ICAM ‐1 Upregulation

“…UA upregulates the polyol pathway, likely through oxidative stress‐induced NFAT5 activation and AKR1B1 activation [ 21 ]. Endogenous fructose production occurs in other tissues such as the liver [ 58 ], and the impact of UA‐polyol pathway interplay on liver disease and endothelial damage is well documented [ 21 , 40 , 41 , 59 , 60 ], and both UA and the polyol pathway are known to mediate activation of the NLRP3 inflammasome [ 61 , 62 ]. In HFs, endogenous fructose may be utilised via GLUT5 and other fructose transporters to promote the Warburg effect to sustain hair growth [ 14 , 63 ].…”

Updated mechanisms of MASLD pathogenesis

“…Various caspase inhibitors (Q-VD-OPh, Belnacasan/VX765) have been pioneered, offering candidate therapeutic strategies for MASLD [ 60 , 61 ]. An aldose reductase inhibitor, epalrestat, acts as the upstream of caspase-1 to inhibit NLRP3 inflammatory vesicles and ameliorate MASH pathology [ 62 ]. Recently, Elodie Bosc et al presented a definitive perspective on caspase-2-specific inhibitors for the treatment of MASLD, while their studies exposed that 3-(S)-neopentyl proline (LJ3a) and 6-methyl-tetrahydro-isoquinoline (LJ2a) inhibited caspase-2-mediated activation of SREBP2 [ 63 ].…”

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

“…We decided to explore targeting the NLRP3 inflammasome with an inhibitor to attempt to rescue the increased susceptibility of BD COs. Currently, MCC950 is the leading compound used to inhibit the NLRP3 activation, however it has been implicated with hepatotoxicity 49,50 . Our group has previously published on the use of a BFE, derived from Euterpe oleracea Mart.…”

“…This drug has been widely considered as an anti-inflammatory alternative to treat NLRP3 induced inflammation, including in autoinflammatory and autoimmune diseases 77 . However growing concerns over hepatotoxicity of MCC950 in phase II clinical trials underlines the need for alternatives 49,50 .…”

Metabolic and Vascular Inflammation in Alopecia Areata: Linking Uric Acid, Lipid Imbalance and ICAM ‐1 Upregulation

“…UA upregulates the polyol pathway, likely through oxidative stress‐induced NFAT5 activation and AKR1B1 activation [ 21 ]. Endogenous fructose production occurs in other tissues such as the liver [ 58 ], and the impact of UA‐polyol pathway interplay on liver disease and endothelial damage is well documented [ 21 , 40 , 41 , 59 , 60 ], and both UA and the polyol pathway are known to mediate activation of the NLRP3 inflammasome [ 61 , 62 ]. In HFs, endogenous fructose may be utilised via GLUT5 and other fructose transporters to promote the Warburg effect to sustain hair growth [ 14 , 63 ].…”

Updated mechanisms of MASLD pathogenesis

“…Various caspase inhibitors (Q-VD-OPh, Belnacasan/VX765) have been pioneered, offering candidate therapeutic strategies for MASLD [ 60 , 61 ]. An aldose reductase inhibitor, epalrestat, acts as the upstream of caspase-1 to inhibit NLRP3 inflammatory vesicles and ameliorate MASH pathology [ 62 ]. Recently, Elodie Bosc et al presented a definitive perspective on caspase-2-specific inhibitors for the treatment of MASLD, while their studies exposed that 3-(S)-neopentyl proline (LJ3a) and 6-methyl-tetrahydro-isoquinoline (LJ2a) inhibited caspase-2-mediated activation of SREBP2 [ 63 ].…”