Background:

Diabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) are major clinical challenges with limited therapeutic options. While these conditions arise from different causes, they may share common molecular mechanisms that could be targeted for intervention.

Methods:

We performed consensus weighted gene co-expression network analysis (WGCNA) on two publicly available datasets: GSE185011 (DPN vs healthy controls in peripheral blood mononuclear cells) and GSE173610 (paclitaxel-treated vs control iPSC-derived sensory neurons). After filtering all but the most variable genes, consensus analysis was used to identify conserved co-expression modules across both conditions.

Results:

Consensus analysis identified a 193-gene module (ME3/brown) significantly associated with both DPN (correlation = 0.817, p = 0.0040) and CIPN (correlation = 0.971, p = 0.0060). Functional enrichment analysis of this module revealed pathways related to Glycolysis, FoxO signaling, Apoptosis, and Autophagy.

Conclusions:

Our analysis reveals a convergent molecular signature underlying both DPN and CIPN, centered on metabolic reprogramming, transcriptional stress, and programmed cell death. These findings provide a systems-level framework for developing therapies targeting shared pathological mechanisms.

Plain language summary

Finding a common link: New research identifies a shared molecular cause for nerve damage from diabetes and chemotherapy, paving the way for universal treatments: Many people with diabetes and cancer patients undergoing chemotherapy suffer from a debilitating condition called peripheral neuropathy. It causes symptoms such as numbness, tingling, and burning pain, typically in the hands and feet. Although the causes are very different (i.e. long-term high blood sugar in diabetes versus toxic drugs in chemotherapy) the symptoms are strikingly similar. Currently, there are no treatments that can reverse the nerve damage, only medicines to help manage the pain. This lack of effective treatments is a major challenge for millions of people. To understand why these two different conditions cause similar problems, our research team looked for a shared root cause at the molecular level. We used a powerful network analysis approach to compare the activity of thousands of genes in two different situations: in blood cells from patients with diabetic neuropathy and in lab-grown nerve cells treated with a chemotherapy drug. Our study found a specific group of 193 genes that were acting in the same way in both conditions. This shared “signature” suggests that both diabetes and chemotherapy trigger the same destructive process in nerve cells. This group of genes suggests a story about what goes wrong inside the damaged nerve cells. It suggests that the cells are facing a severe energy crisis, struggling to produce the fuel they need to survive. This crisis may then activate a major stress response pathway, possibly controlled by a “master-switch” gene. Instead of helping the cell recover, this response seems to go haywire, ultimately turning on the cell’s own self-destruct and recycling programs. This process leads to nerve damage and eventual cell death that causes the debilitating symptoms of neuropathy. The discovery of this common pathway is a significant step forward. It suggests that instead of developing separate treatments for neuropathy caused by diabetes and neuropathy caused by chemotherapy, we might be able to create a single, universal therapy. By targeting the key genes in this shared pathway, it may be possible to protect nerve cells from damage, regardless of the initial cause. This research opens a new door for developing treatments that could prevent or even reverse this debilitating condition for a wide range of patients.