Oxygen is an essential molecule for life on Earth, and its deficiency poses a significant threat to the maintenance of life. Under the hypoxic conditions, hypoxia-inducible factors (HIFs) rapidly accumulate within cells, functioning as transcription factors to regulate gene expression and mitigate cellular stress caused by low oxygen levels. However, within living tissues, hypoxic environments are increasingly recognized as important signaling factors necessary for regulating tissue homeostasis and activating specific cellular functions. For example, we have reported that fibroblasts not only survive but actively become more activated in hypoxic environments, which paradoxically promotes cardiac fibrosis (AJRCMB 2018;58:216, Int Heart J 2019;60:958）. Another example is the activation of macrophage efferocytosis, the process of clearing dead cells that is crucial for resolving inflammation, is accelerated under the hypoxic conditions. These observations cannot be fully explained by classical models of cellular energy production with the electron transport chain and glycolysis. We are therefore employing a multi-faceted approach, utilizing advanced optical imaging techniques, novel genetic animal models and omics analysis, to uncover the role of oxygen signaling in interstitial cells in living tissues.