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Lipoxygenase (LOX) family of enzymes involved in pathogenesis of diseases

Isozymes of LOX

ALOX12

( expressed in pancreas)

β islet function

Lipoxygenases (LOX)

+

Arachidonic acid

(fatty acid crucial to brain/muscle function and inflammation)

Inflammatory and mitogenic signaling molecules

ALOX15

(Expressed in brain)

Brain injury

ALOX12

12-Lipoxygenase (ALOX12) is produced by various sites including pancreatic islets, vascular cells, macrophages and platelets. The ALOX12 lipid products of arachidonic acid (12-oxylipins) lead to oxidative and endoplasmic reticulum (ER) stress and macrophage activation.

In Type 1 Diabetes the 12-oxylipins mediates cytokine induced beta cell dysfunction and death. Genetic deletion of 12-LOX in mouse models improves insulin signaling and prevents diabetes development. In Pancreatic Cancer, ALOX12 produces 12(S)-HETE, which acts as a mitogen, stimulating PDAC cell growth, migration, and invasion. The ALOX12/12-HETE/GPR31 pathway promotes the polarization of tumor-associated macrophages (M2 type), which further supports cancer progression. Overexpression of ALOX12 leads to high levels of 12(S)-HETE, directly promoting cancer cell proliferation.

ALOX15

In stroke, the enzyme 15-lipoxygenase (ALOX15) is a key driver of secondary brain damage, promoting oxidative stress, neuronal death, blood-brain barrier breakdown, and edema in the penumbra (salvageable tissue) by damaging mitochondria.

How ALOX15 contributes to stroke damage:

•Oxidative Stress & Mitochondrial Damage: ALOX15 generates reactive oxygen species (ROS) and directly damages neuronal mitochondria, triggering cell death pathways.
•Neuronal Death: It acts as a central executor in oxidative stress-related neuronal death, particularly in the vulnerable penumbra, leading to delayed cell death.
•Blood-Brain Barrier (BBB) Weakening: Increased ALOX15 activity contributes to BBB disruption, worsening edema and overall injury.
•Neuroinflammation: It promotes inflammatory lipid mediators and pathways, exacerbating tissue damage after the initial ischemic event.