EXPRESS: Regulatory Effects of Lactate and HIF-1α Signaling Axis in the Chronic Wound Microenvironment

Chronic wounds represent a major unmet clinical challenge that imposes substantial global healthcare burden, as their pathological mechanisms remain incompletely targeted by existing therapies. Sustained local hypoxia and progressive lactate accumulation are two well-validated, interlinked pathological hallmarks that drive persistent non-healing phenotypes across different etiologies of chronic wounds. Most existing reviews separately describe the regulatory roles of lactate or HIF-1α in wound repair, but few systematically integrate their bidirectional feedback loop and context-dependent, stage-specific effects on multiple reparative cell populations. This narrative review synthesizes current preclinical and clinical evidence to map the complete reciprocal regulatory cascade between lactate and HIF-1α, clarifies their distinct, dose-dependent modulatory effects on fibroblasts, epidermal keratinocytes, and macrophages, and explicitly explains how their self-amplifying signaling loop locks chronic wounds in a sustained inflammatory-metabolic vicious cycle. We further stratify all reported therapeutic interventions along the full lactate-HIF-1α signaling axis, clearly separating preclinically validated strategies from preliminary mechanistic observations and unresolved open questions in the field. This work provides a refined, context-aware reference framework to support the design of stage-matched, precision metabolic therapies for chronic non-healing wounds.