Hyaluronic acid-FGF2-derived peptide bioconjugates for suppression of FGFR2 and AR simultaneously as an acne antagonist

Abstract

Acne is a chronic skin condition that has serious consequences for mental and social well-being because it frequently occurs on the face. Several acne treatment approaches have commonly been used but have been hampered by side effects or weak activity. Thus, the investigation of the safety and efficacy of anti-acne compounds is of considerable medical importance. Herein, an endogenous peptide (P5) derived from fibroblast growth factors 2 (FGF2) was conjugated to the polysaccharide hyaluronic acid (HA) to generate the bioconjugate nanoparticle HA-P5, which suppresses fibroblast growth factor receptors (FGFRs) to significantly rehabilitate acne lesions and reduce sebum accumulation in vivo and in vitro. Moreover, our results show that HA-P5 inhibits both fibroblast growth factor receptor 2 (FGFR2) and androgen receptor (AR) signalling in SZ95 cells, reverses the acne-prone transcriptome, and decreases sebum secretion. Furthermore, the cosuppression mechanism revealed that HA-P5 blocks FGFR2 activation, as well as the YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) downstream molecules, including an N6-methyladenosine (m6A) reader that facilitates AR translation. More importantly, a significant difference between HA-P5 and the commercial FGFR inhibitor AZD4547 is that HA-P5 does not trigger the overexpression of aldo-keto reductase family 1 member C3 (AKR1C3), which blocks acne treatment by catalyzing the synthesis of testosterone. Overall, we demonstrate that a polysaccharide-conjugated and naturally derived oligopeptide HA-P5 can alleviate acne and act as an optimal FGFR2 inhibitor and reveal that YTHDF3 plays a crucial role in signalling between FGFR2 and AR. Graphical Abstract

Significance of N6-methyladenosine RNA methylation regulators in diagnosis and subtype classification of primary Sjögren’s syndrome

“…Results from our study indicate that the YTHDF3/YTHDF1 complex greatly improves the translation of PSS mRNA. This is similar to the study by Su et al [ 31 ]. Xue et al [ 32 ] have successfully identified IGF2BP1 as a conserved single-stranded RNA-binding protein, which involved in gene expression regulation and is associated with the onset and progression of inflammation.…”

RNA methylation‐related inhibitors: Biological basis and therapeutic potential for cancer therapy

“…For example, a biologically coupled nanoparticle called HA‐P5 was generated by coupling an FGF2‐derived endogenous peptide (P5) to HA polysaccharide. This nanoparticle inhibits downstream molecules of YTHDF3 in SZ95 cells 158 . However, several unresolved issues persist.…”

“…This nanoparticle inhibits downstream molecules of YTHDF3 in SZ95 cells. 158 However, several unresolved issues persist. First, our current knowledge does not allow for the precise determination of the spatiotemporal modification of the transcriptome in question.…”

SAIF plays anti-angiogenesis via blocking VEGF-VEGFR2-ERK signal in tumor treatment

“…Cell proliferation assay was performed as previously described [ 24 ]. HUVECs or cancer cells (2.5 × 10 3 per well/100 μL) were seeded into 96-well plates with ECM medium.…”