<p>Keratoconus (KC) is a progressive corneal disorder characterized by thinning of the cornea and conical protrusion leading to distorted vision and blindness. The disease often marks in adolescence and progresses until the mid-40s, with varying degrees of severity. Global prevalence shows regional variation, with higher rates in Asian populations and strong associations with systemic conditions such as Down syndrome. The current study investigates the underlying pathological mechanism with a focus on biomarkers, including Prolactin-Induced Protein (PIP), Matrix Metalloproteinases (MMPs), Interleukins, and genetic markers as LOX and FOXO1. While the clinical appearance may be highly variable with relevant distorted vision, the pathophysiology remains poorly understood. Generally, it affects teenagers, young adults, and has been related to pathological factors like oxidative stress, environmental influences, hormonal changes, and eye rubbing. Although with the progress of diagnostic modalities from corneal topography and tomography to tear-based assays and artificial intelligence, it is still a challenge to diagnose it early. The involvement of systemic and local inflammatory responses in KC is now an area of increasing interest, implying that targeting these pathways will provide new treatment options. Besides, progress in tear-based diagnostics offers promising paths for non-invasive monitoring of disease progression. Clarifying the biochemical and genetic profile of keratoconus may help to focus on better diagnosis. The present review will increase our insights into keratoconus pathophysiology and encourage new diagnostic and therapeutic strategies that can eventually enhance patient outcomes.</p> Graphical abstract <p></p>