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Background <p>Diabetic foot ulcers (DFUs) are prevalent complication in diabetes. METTL14 serves as a key regulator of both autophagy and pyroptosis, both essential for the healing of DFUs. Simiao Yong'an Decoction (SYD) has demonstrated potential in promoting skin wound healing. This study investigates how METTL14 functions as a main regulator in DFU wound healing during SYD treatment and explores the underlying mechanisms.</p> Methods <p>Both qPCR and western blot assays were performed to determine METTL14 and BECN1 expression. DFU rat models and fibroblasts stimulated with high glucose (HG) were used to evaluate the role of METTL14 in autophagy, pyroptosis, pro-angiogenic ability, and wound healing through both loss- and gain-of-function assays. The association between METTL14 and BECN1 was examined via MeRIP and RNA stability assays. Futhermore, the therapeutic effects of SYD on DFUs were assessed.</p> Results <p>Exposure to HG reduced METTL14 levels in fibroblasts, resulting in reduced cell viability and migration, lowered autophagy, and increased pyroptosis. Increasing METTL14 expression reversed these cellular impairments and enhanced angiogenesis driven by fibroblasts. Mechanistically, METTL14 stabilized BECN1 mRNA via m<sup>6</sup>A modification. In a rodent DFU model, overexpression of METTL14 accelerated wound healing, improved angiogenesis, and regulated autophagy and pyroptosis; these beneficial effects were partially reversed when BECN1 was knocked down. Furthermore, treatment with SYD increased METTL14 expression, promoted wound closure, angiogenesis, and autophagy, while reducing pyroptosis; these positive outcomes were significantly reduced when METTL14 was knocked down.</p> Conclusions <p>METTL14-mediated m<sup>6</sup>A modification of BECN1 influences autophagy, pyroptosis, and angiogenesis to enhance wound healing in DFUs. METTL14 serves as a key regulator in SYD-mediated wound repair, offering a novel therapeutic strategy for treating DFUs.</p> Graphical Abstract <p></p>

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METTL14 modulates the autophagy-pyroptosis pathway in fibroblasts by modifying BECN1 through m6A methylation to promote wound healing in DFUs and SYD treatment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月1日

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  • Zhaowei Wang,
  • Zongqiang Wei,
  • Qinyao Yu,
  • Linru Wang,
  • Kai Liu,
  • Hongjie Wang,
  • Qiang Li

摘要

Background

Diabetic foot ulcers (DFUs) are prevalent complication in diabetes. METTL14 serves as a key regulator of both autophagy and pyroptosis, both essential for the healing of DFUs. Simiao Yong'an Decoction (SYD) has demonstrated potential in promoting skin wound healing. This study investigates how METTL14 functions as a main regulator in DFU wound healing during SYD treatment and explores the underlying mechanisms.

Methods

Both qPCR and western blot assays were performed to determine METTL14 and BECN1 expression. DFU rat models and fibroblasts stimulated with high glucose (HG) were used to evaluate the role of METTL14 in autophagy, pyroptosis, pro-angiogenic ability, and wound healing through both loss- and gain-of-function assays. The association between METTL14 and BECN1 was examined via MeRIP and RNA stability assays. Futhermore, the therapeutic effects of SYD on DFUs were assessed.

Results

Exposure to HG reduced METTL14 levels in fibroblasts, resulting in reduced cell viability and migration, lowered autophagy, and increased pyroptosis. Increasing METTL14 expression reversed these cellular impairments and enhanced angiogenesis driven by fibroblasts. Mechanistically, METTL14 stabilized BECN1 mRNA via m6A modification. In a rodent DFU model, overexpression of METTL14 accelerated wound healing, improved angiogenesis, and regulated autophagy and pyroptosis; these beneficial effects were partially reversed when BECN1 was knocked down. Furthermore, treatment with SYD increased METTL14 expression, promoted wound closure, angiogenesis, and autophagy, while reducing pyroptosis; these positive outcomes were significantly reduced when METTL14 was knocked down.

Conclusions

METTL14-mediated m6A modification of BECN1 influences autophagy, pyroptosis, and angiogenesis to enhance wound healing in DFUs. METTL14 serves as a key regulator in SYD-mediated wound repair, offering a novel therapeutic strategy for treating DFUs.

Graphical Abstract