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Other Small Molecular Targets The receptor activation of cannabinoid (CB)-1/2 involves the production of endocannabinoids, subsequently, endocannabinoids are quickly metabolized by specific fatty acid amide hydrolase (FAAH) (176)

Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE: Steroid 5-reductase deficiency in man: An inherited form of male pseudohermaphroditism.Sciences1994,186, 1213-1215 59

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TGF- is another pivotal cytokine in ALD, primarily involved in liver fibrosis, one of the hallmarks of chronic liver injury.88 Ethanol and its metabolite, acetaldehyde, increase the expression of TGF-1 in HSCs, activating them to produce ECM proteins such as collagen, which leads to the accumulation of fibrotic tissue in the liver.89 In addition to its fibrogenic effects, TGF- inhibits matrix-degrading proteolytic enzymes, further contributing to fibrosis by preventing the breakdown of the ECM.89 TGF- also exerts direct effects on hepatocytes, inducing apoptosis and inhibiting proliferation, which exacerbates liver injury and impairs the livers ability to regenerate following damage.90 91 Furthermore, TGF- influences immune cell function by polarising macrophages towards an M2 phenotype, which is associated with tissue remodelling and fibrosis.92 Despite its central role in fibrosis, TGF- exhibits complex and sometimes contradictory effects.93 94 While it promotes fibrogenesis, it can also have anti-inflammatory and tissue repair functions.93 This multifunctional nature presents a significant challenge in targeting TGF- as a therapeutic strategy for ALD