Unveiling hepatic Krüppel-like factor 15 as the key regulator of cyclosporine A metabolism and adverse effects.

Cyclosporine A (CsA) is a widely used immunosuppressant for posttransplantation and autoimmune diseases, but its clinical application is limited by severe hepatorenal toxicity. Krüppel-like factor 15 (KLF15), a key regulator of xenobiotic metabolism, has been shown to modulate the metabolism of acetaminophen and rifampicin and play a role in the associated drug-induced liver toxicity. However, its role in CsA metabolism and CsA-induced hepatorenal injury remains unclear. This study aimed to investigate whether hepatic KLF15 regulates CsA metabolism and serves as a potential therapeutic target for mitigating CsA-induced hepatorenal toxicity. KLF15 broadly suppressed the CsA detoxification pathways by inhibiting key metabolic enzymes and transporters. Inhibition of hepatic KLF15 enhanced CsA detoxification, reduced CsA accumulation, and prevented hepatorenal injury. Notably, both AAV-shKlf15 and PXR agonist treatment demonstrated protective effects even after CsA-induced organ damage had occurred. These findings highlight KLF15 as a critical regulator of CsA metabolism and a promising therapeutic target for preventing or treating CsA-induced hepatorenal toxicity. The study provides preclinical evidence supporting further exploration of KLF15 modulation in clinical settings. SIGNIFICANCE STATEMENT: Hepatic Krüppel-like factor 15 is critical in regulating the metabolism of acetaminophen, rifampicin, and cyclosporine A, drugs used for pain relief, antibiotics, and immune system regulation, respectively. It may serve as a potential therapeutic target for liver and kidney damage induced by these drugs.