In a letter published by her France-based son Mahmoud Moradkhani on Twitter, Badri Hosseini Khamenei indicted the Iranian leader for "not listening to the voice of the people."
"As a human duty, many years ago, I repeatedly brought the voices of the people to the ears of my brother, but he didn't pay any heed and followed (Islamic Republic founder Ayatollah) Khomeini's way in suppressing and killing people," she wrote in the letter, adding that she later cut her ties with him.
Iran has seen widespread protests in recent months following the death of a 22-year-old woman, Mahsa Amini, in the custody of Iranian morality police.
Thousands of people have been detained, according to human rights groups, while more than 200 people have died, as acknowledged by the Iranian Interior Ministry last week.
Extending her support to the anti-government protests, Badri Hosseini said the Islamic Revolutionary Guard Corps (IRGC) must lay down their arms "as soon as possible" and "join the people."
The veracity of the letter has not been independently attested, and Khamenei's sister also has not publicly spoken about it.
It comes days after reports emerged that Badri Hosseini’s daughter and the Iranian leader's niece has been arrested in Tehran over anti-government remarks.
Faridah Muradkhani had published a video before her arrest comparing the Iranian leader to "Hitler and Mussolini", while calling for the international community's intervention.
"When they can arrest my daughter in violent fashion, it is clear that they apply thousands of times more violence to the oppressed sons and daughters of others," her mother wrote in the letter.
Badri Hosseini was married to a prominent Iranian cleric Sheikh Ali Tehrani, who died last month at the age of 96.
Tehrani, who took active part in the 1979 revolution, later developed differences with key figures of the revolution and became a staunch critic of the Islamic Republic.
Many Western governments have imposed sanctions on Iran in recent months, while authorities in Tehran have accused the Western states of fomenting unrest in the country.
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