Currently, chronic kidney disease (CKD) is one of the most common diseases; it is also a serious threat to human health due to its high mortality, and its treatment is still a major clinical challenge. Mitochondrial dyshomeostasis plays an important role in the development of CKD. ZLN005 is a novel peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) activator from our laboratory. To explore whether ZLN005 can protect against CKD in vivo and in vitro, a unilateral ureteral obstruction (UUO) model and TGF-β1-treated renal tubular epithelial cells (TECs), respectively, were used in this study. We found that ZLN005-administrated UUO mice showed less kidney damages than control mice, as indicated by the reduced expression of fibrotic biomarkers in the kidney of UUO mice. ZLN005 treatment also alleviated the TGF-β1-induced fibrotic phenotype and lipid accumulation in TECs. Our study demonstrated ZLN005 treatment improved mitochondrial homeostasis at least partially via the activation of PGC-1α, thus maintaining mitochondria function and energy homeostasis. In summary, ZLN005 treatment ameliorates UUO-induced renal fibrosis, providing conceptional support for mitochondria-targeting therapies for chronic kidney disease.

Acute liver injury (ALI) is a potentially life-threatening condition lacking effective clinical drugs. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of both inflammation and metabolism. In ALI, HIF-1α expressions are upregulated, but the role of HIF-1α in hepatocytes and whether it can be targeted remain unclear. Herein, clinical samples and ALI murine models including lipopolysaccharide/D-galactosamine (LPS/D-GalN), acetaminophen (APAP), and thioacetamide (TAA) revealed an increase in HIF-1α expression and ferroptosis. Using HIF-1α gain and loss of function mouse and hepatocyte culture models, we demonstrated that HIF-1α upregulation exacerbated liver ferroptosis and injury. Mechanistically, HIF-1α/transferrin receptor protein 1 (TFR1) axis drives hepatic iron overload, promoting ferroptotic cell death and liver injury. In addition, TFR1 inhibition reversed HIF-1α-induced ALI. Importantly, pharmacological inhibition of HIF-1α and TFR1 significantly reduced ferroptosis and mitigated liver injury both in vivo and in vitro. Together, our findings demonstrate the pathological role of hepatic HIF-1α, which may serve as a promising target of therapeutic intervention.

Glycosylation serves as an effective strategy to enhance the solubility, bioavailability, and pharmacological activity of polyhydroxyphenols. In this study, we explored the glycosylation of natural and natural-inspired phenolic compounds using the glycosyltransferase AbCGT and evaluated the anti-renal fibrotic potential of the resulting glycosides. Among them, 1,3,5,8-tetrahydroxyxanthone 5-O-β-D-glucopyranoside (2-1a), synthesized via the regioselective 5-O-glycosylation of demethylbellidifolin, demonstrated significant anti-renal fibrotic activity. In contrast, its homologous glycosyltransferase, UGT73AE1, predominantly glycosylated demethylbellidifolin at the 3-OH position. Molecular docking studies revealed the structural basis for this regioselectivity difference. To enhance the production of 2-1a, we established a UDP-glucose (UDPG) recycling system by coupling AbCGT with Glycine max sucrose synthase (GmSuSy) and subsequently optimized the reaction conditions. Furthermore, targeted mutagenesis of AbCGT informed by molecular docking analysis identified a F138A mutant that enhanced glycosylation yield by 2.3-fold. This work develops a novel glycosyltransferase-based catalytic system and identifies a new compound with potential anti-renal fibrotic activity.