Mystery behind Botticelli’s Birth of Venus side-eye solved — and the reason is heartbreaking

For more than 500 years, Venus’ sideways glance has sparked endless debate.

Now, scientists believe Sandro Botticelli wasn’t taking artistic license at all in his iconic “Birth of Venus” painting.

The legendary artist may have faithfully painted the subtle signs of the devastating illness that killed his muse decades before modern medicine could explain it.

Researchers now believe it reflected a devastating real-life medical condition suffered by the woman who inspired one of history’s most famous paintings.

The subject is widely believed to be Simonetta Vespucci, the legendary Florentine beauty who captivated Renaissance Italy — and apparently Botticelli himself.

Scientists from Queen Mary University of London say her slightly misaligned gaze may have been caused by a pituitary adenoma, a usually benign brain tumor that grows on the pituitary gland.

The findings build on a theory the team first proposed seven years ago.

After reviewing additional historical documents, the researchers now believe an expanding pituitary tumor likely caused the medical emergency that claimed Simonetta’s life at just 23 — overturning the long-held belief that she died of tuberculosis.

“It’s possible that the irregular eye positioning in the Birth of Venus – the ‘strabismus’ or squint later considered a trait of piety and beauty – may be caused by the pituitary tumor,” senior author Paolo Pozzilli said in the new study.

According to the researchers, Simonetta may have experienced tumor apoplexy — a dangerous condition in which bleeding or swelling inside the tumor becomes a medical emergency.

For centuries, art historians largely chalked Venus’ wandering eye up to symbolism, suggesting Botticelli intentionally painted it as a sign of beauty or religious devotion.

But after analyzing five portraits believed to depict Simonetta using facial recognition software, the researchers concluded the feature may have been hiding in plain sight.

The AI-assisted analysis also bolstered their earlier theory that she suffered from a hormone-secreting pituitary tumor.

The team believes the same tumor may also explain the tragic death of Simonetta, who died at just 23 years old after suffering a sudden medical emergency.

“Letters between Piero Vespucci and Lorenzo de’ Medici about Simonetta’s final days discuss how she collapsed during a ball and was then resting in a darkened room where she suffered from terrible headaches, hallucinations, vomiting and high fever,” said first author Dr. Domiziana Nardelli.

“These are all symptoms of a rapidly expanding pituitary tumor.”

They also speculate that vigorous dancing at the ball — or, more grimly, an alleged assault by Alfonso II d’Aragona, Duke of Calabria — could have triggered the fatal episode.

The facial analysis also pointed to another possible clue.

“Botticelli’s Allegorical portrait of a Woman shows a woman – the model is Simonetta Vespucci – lactating, and yet we know she had no children,” Nardelli said.

“This is a surprising way to portray her, and we believe that this – along with changes in facial traits – could show the real physical symptoms of a prolactin-growth hormone-secreting adenoma.”

Known to Renaissance society as “La Sans Par,” or “The Unrivalled,” Simonetta was celebrated for her beauty, intellect and grace, becoming one of Florence’s most admired women despite her short life.

Botticelli’s fascination with her endured long after her death. So devoted was the artist to his muse that he requested to be buried at her feet when he died in 1510 — a final tribute to the woman whose face would become one of the most recognizable in the history of art.

It turns out that Venus wasn’t just giving the world side-eye. She may have been quietly revealing a heartbreaking diagnosis all along.

The discovery comes months after another Renaissance mystery made headlines.

As The Post previously reported in November, a dusty painting that spent years tucked beneath a garage workbench sold for roughly $750,000 after experts identified it as a long-lost work by Pietro Perugino — a celebrated Renaissance painter who worked alongside Botticelli on the Sistine Chapel between 1480 and 1482.

The forgotten “Madonna and Child” piece sparked an international bidding war after surfacing at a small English auction house, with collectors driving the final price to £685,000.

“When the hammer fell, there was a hush, then applause,” auctioneer Joe Smith said. “It was one of those moments every auctioneer dreams of.”