Pope Leo XIV issued a fervent appeal for return of diplomacy in "these dramatic hours" in the Middle East and Iran, condemning use of weapons that cause "destruction, pain, and death."

Pope Leo spoke roughly 12 hours after the U.S. and Israel revealed that Iran's supreme leader, 86-year-old Ayatollah Ali Khamenei, is among the country's senior leaders killed in their initial assault on Iran, started in the early morning hours on Feb. 28.

During his Sunday Angelus prayer March 1, the Pope said he was "following with profound concern" these events and warned of a potential "tragedy of enormous proportions." He appealed for the warring parties to assume "the moral responsibility of halting the spiral of violence" before it becomes "an irreparable abyss."

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The Pope insisted the nations return to diplomacy.

"Stability and peace are not built through mutual threats, nor with weapons that sow destruction, pain and death, but only through reasonable, authentic and responsible dialogue," he said.

The ongoing joint U.S. and Israeli attack on Iran has targeted Tehran and cities across Iran, with Gulf countries caught in the crossfire as Iran launches retaliatory strikes.

"Faced with the possibility of a tragedy of enormous proportions, I address to the parties involved a heartfelt appeal to assume the moral responsibility of halting the spiral of violence before it becomes an irreparable abyss," he said.

"May diplomacy regain its role and promote the good of the peoples who yearn for peaceful coexistence based on justice," he added, urging the world to "continue to pray for peace."

What Pope Leo called a "spiral of violence" continued to unfold Sunday as mutual attacks escalated hour by hour throughout the Middle East.

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Israel and Iran launched fresh attacks March 1, leaving 555 people dead, according to the Iranian Red Crescent Society as reported by Associated Press.

Israel's military said on X March 1 that its strikes have killed 40 Iranian commanders, including Abdolrahim Mousavi, the chief of staff of Iran's armed forces. Iranian state television confirmed the death.

In the conflict's opening 24 hours, two people were killed in Tel Aviv as an Iranian missile hit a residential building, while 120 people in Israel were injured from Iran's counterstrikes, The Jerusalem Post reported.

The Guardian reported Iran's president, Masoud Pezeshkian, was quoted as having called the killing of Iran's supreme leader "an open war against Muslims" and having said that Iran "considers bloodshed and revenge against the perpetrators and commanders of this crime as its legitimate duty and right, and will fulfill this great responsibility and duty with all its might."

Iran's ally, Russia, condemned Khamenei's killing, with President Vladimir Putin saying that the "murder" of Khamenei was a "cynical violation of all norms of human morality."

U.S. President Donald Trump took to Truth Social on March 1 warning Iran to not retaliate further.

"Iran just stated that they are going to hit very hard today, harder than they have ever hit before," Trump wrote on his social network. He added, "THEY BETTER NOT DO THAT, HOWEVER, BECAUSE IF THEY DO, WE WILL HIT THEM WITH A FORCE THAT HAS NEVER BEEN SEEN BEFORE!"

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Pope Leo, during his Angelus appeal, reminded people that in recent days, "we have also received disturbing news of clashes between Pakistan and Afghanistan." He raised a "plea for an urgent return to dialogue."

"Let us pray together that harmony may prevail in all the world's conflicts," he said, adding, "Only peace, a gift of God, can heal the wounds between peoples."